Sulfur substituted sulfonylaminocarboxylic acid N-arylamides, their preparation, their use and pharmaceutical preparations comprising them

ABSTRACT

The present invention relates to compounds of the formula I                    
     wherein A 1 , A 2 , R 1 , R 2 , R 3 , X and n are as defined in the claims, which are valuable pharmaceutically active compounds for the therapy and prophylaxis of diseases, for example of cardiovascular diseases such as hypertension, angina pectoris, cardiac insufficiency, thromboses or atherosclerosis. The compounds of the formula I are capable of modulating the body&#39;s production of cyclic guanosine monophosphate (cGMP) and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention furthermore relates to processes for preparing compounds of the formula I, to their use for the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose, and to pharmaceutical preparations which comprise compounds of the formula I.

The present application claims priority under 35 U.S.C. § 119 to Germanpatent applications No. 19830430.7 filed Jul. 8, 1998, and No.19903126.6 filed Jan. 27, 1999. Both priority applications are entirelyincorporated herein by reference.

The present invention relates to compounds of the formula I

wherein A¹, A², R¹, R², R³, X and n are as defined below, which arevaluable pharmaceutically active compounds for the therapy andprophylaxis of diseases, for example for cardiovascular diseases such ashypertension, angina pectoris, cardiac insufficiency, thromboses oratherosclerosis. The compounds of the formula I are capable ofmodulating the body's production of cyclic guanosine monophosphate(“cGMP”) and are generally suitable for the therapy and prophylaxis ofdiseases which are associated with a disturbed cGMP balance. Theinvention furthermore relates to processes for preparing compounds ofthe formula I, to their use for the therapy and prophylaxis of theabovementioned diseases and for preparing pharmaceuticals for thispurpose, and to pharmaceutical preparations which comprise compounds ofthe formula I.

cGMP is an important intracellular messenger which triggers a multitudeof different effects via the modulation of cGMP-dependent proteinkinases, phosphodiesterases and ion channels. Examples are therelaxation of smooth muscles, the inhibition of thrombocyte activationand the inhibition of the proliferation of smooth-muscle cells and ofleukocyte adhesion. cGMP is produced by particulate and solubleguanylate cyclases as a response to a number of extracellular andintracellular stimuli. In the case of the particulate guanylatecyclases, stimulation is essentially effected by peptidic messengers,such as the atrial natriuretic peptide or the cerebral natriureticpeptide. The soluble guanylate cyclases (“sGC”), which are cytosolicheterodimeric heme proteins, in contrast, are essentially regulated by afamily of low-molecular-weight factors which are formed enzymatically.The most important stimulant is nitrogen monoxide (“NO”) or a closelyrelated species. The function of other factors such as carbon monoxideor the hydroxyl radical is still largely unclear. The binding of NO tothe heme with formation of a penta-coordinate heme-nitrosyl complex isbeing discussed as activation mechanism of the activation by NO. Theassociated release of the histidine which is bound in the basal state tothe iron converts the enzyme into the active conformation.

Active soluble guanylate cyclases are composed of an α and a β subuniteach. Several subunit subtypes have been described which differ from oneanother with respect to sequence, tissue-specific distribution andexpression in different development stages. The subtypes α₁ and β₁ aremainly expressed in brain and lung, while β₂ is found in particular inliver and kidney. The subtype α₂ was shown to be present in human fetalbrain. The subunits referred to as α₃ and β₃ were isolated from humanbrain and are homologous to α₁ and β₁. More recent works indicate anα_(2i) subunit which contains an insert in the catalytic domain. Allsubunits show great homologies in the region of the catalytic domain.The enzymes presumably contain one heme per heterodimer, which is boundvia β₁-Cys-78 and/or β₁-His-105 and is part of the regulatory center.

Under pathologic conditions, the formation ofguanylate-cyclase-activating factors can be reduced, or theirdegradation may be promoted owing to the increased occurrence of freeradicals. The resulting reduced activation of the sGC leads, via aweakening of the respective cGMP-mediated cellular response, for exampleto an increase of the blood pressure, to platelet activation or toincreased cell proliferation and cell adhesion. As a consequence,formation of endothelial dysfunction, atherosclerosis, hypertension,stable or unstable angina pectoris, thromboses, myocardial infarction,strokes or erectile dysfunction results. Pharmacological stimulation ofsGC offers a possibility to normalize cGMP production and thereforemakes possible the treatment and/or prevention of such disorders.

For the pharmacological stimulation of the sGC, use has hitherto almostexclusively been made of compounds whose activity is based on anintermediate NO release, for example organic nitrates. The drawback ofthis treatment is the development of tolerance and a reduction ofactivity, and the higher dosage which is required because of this.

Various sGC stimulators which do not act via NO release were describedby Vesely in a series of publications. However, the compounds, most ofwhich are hormones, plant hormones, vitamins or natural compounds suchas, for example, lizard poisons predominantly only have weak effects onthe cGMP formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest.,vol.15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol.88, 1979, p.1244. A stimulation of heme-free guanylate cyclase byprotoporphyrin IX was demonstrated by Ignarro et al., Adv. Pharmacol.,vol. 26, 1994, p. 35. Pettibone et al., Eur. J. Pharmacol., vol. 116,1985 p. 307, described an antihypertensive action of diphenyliodoniumhexafluorophosphate and attributed this to a stimulation of sGC.According to Yu et al., Brit. J. Pharmacol, vol. 114, 1995, p.1587,isoliquiritigenin, which has a relaxing action on isolated rat aortas,also activates sGC. Ko et al., Blood vol. 84, 1994, p. 4226, Yu et al.,Biochem. J. vol. 306, 1995, p. 787, and Wu et al., Brit. J. Pharmacol.vol. 116, 1995, p. 1973, demonstrated a sGC-stimulating activity of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated anantiproliferative and thrombocyte-inhibiting action. Pyrazoles and fusedpyrazoles which exhibit a sGC-stimulating activity are described inEuropean Patent Application No. 908,456 and German Patent ApplicationNo. 19,744,027.

A series of 2-sulfonylaminobenzoic acid N-arylamides, the N-aryl groupof which carries a thio substituent, have been mentioned in theliterature. These compounds in which the N-aryl group generally carriesas further substituents groups which are readily oxidizable such as, forexample, two hydroxy groups being in para position with respect to oneanother and which in this case can be regarded as hydroquinonederivatives, are auxiliaries for the preparation of photographicmaterials (see, for example, Chemical Abstracts 119, 105757; 120, 41858;123, 70224; or 126, 257007). If isolated structural elements areconsidered then the N-aryl group in these known compounds corresponds tothe group R¹—S(O)_(n)—A¹ in formula I in case A¹ denotes a 1,4-phenyleneresidue which in positions 2 and 5 carries hydroxy groups (or oxysubstituents), and the number n is 0. British patent publication No.876,526 (Chemical Abstracts 56, 15432e) discloses3,5-dichloro-2-methylsulfonylaminobenzoic acidN-(5-chloro-2-(4-chlorophenylmercapto)-phenyl)-amide which can be usedfor the protection of wool against moths. Compounds covered by Britishpatent publication No. 876,526 correspond to compounds of the formula Iif simultaneously the ring A¹ which comprises the carbon atoms whichcarry the groups C(═X)—NH— and NH—SO₂R², together with the residues R³,is a benzene ring which carries one to four halogen atoms from theseries chlorine and bromine, R² is (C₁-C₄)-alkyl, X is oxygen and thegroup R¹—S(O)_(n)—A¹— is a phenylmercaptophenyl-residue(=phenylthiophenyl-) which is substituted by halogen and/ortrifluoromethyl and which can also be substituted by methyl or(C₁-C₄)-alkoxy, and the total number of halogen atoms andtrifluoromethyl groups is greater than two. Pharmacological activitiesof these known 2-sulfonylaminobenzoic acid N-arylamides are notdisclosed.

Surprisingly, it has now been found that the compounds of the presentinvention effect a strong activation of guanylate cyclase and aretherefore suitable for the therapy and prophylaxis of disorders whichare associated with a low cGMP level.

Thus, the present invention relates to compounds of the formula I:

wherein

A¹ is a divalent residue from the series phenylene, naphthylene andheteroarylene which can all be substituted by one or more identical ordifferent substituents from the series halogen, (C₁-C₅)-alkyl, phenyl,tolyl, CF₃, NO₂, OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl and—S(O)_(n)-tolyl;

the ring A² which comprises the carbon atoms which carry the groupsC(═X)—NH— and NH—SO₂R² is a benzene ring, a naphthalene ring, asaturated or partially unsaturated 3-membered to 7-membered carbocycle,a saturated or partially unsaturated or aromatic monocyclic 5-memberedto 7-membered heterocycle which contains one or more ring heteroatomsfrom the series N, O and S, or a saturated or partially unsaturated oraromatic bicyclic 8-membered to 10-membered heterocycle which containsone or more ring heteroatoms from the series N, O and S;

R¹ is aryl, heterocyclyl or (C₁-C₁₈)-alkyl which can be substituted byone or more identical or different residues R⁴ or, if the number n inthe group R¹—S(O)_(n)— is 2, R¹ can also be NR⁵R⁶ or, if the number n inthe group R¹—S(O)_(n)— is O, R¹ can also be —CN;

R² is aryl, heterocyclyl, NR⁵R⁶ or (C₁-C₁₀)-alkyl which can besubstituted by one or more identical or different residues R⁴;

R³ denotes one or more identical or different residues from the serieshydrogen, halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—ON, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl and (C₁-C₅)-alkyl which can be substituted byone or more identical or different residues R⁴;

R⁴ is fluorine , OH, —O—(C₁-C₁₀)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, —CN, NR⁷R⁸, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, heterocyclyl or oxo;

R⁵ is hydrogen, (C₁-C₁₀)-alkyl which can be substituted by one or moreidentical or different substituents R⁴ and/or by aryl, or is aryl,heterocyclyl, —CO—NR⁷R⁸, —CO-aryl or —CO—(C₁-C₁₀)-alkyl wherein thealkyl residue can be substituted by one or more identical or differentresidues R⁴;

R⁶ independently of R⁵ has one of the meanings indicated for R⁵, or

R⁵ and R⁶ together with the nitrogen atom to which they are bonded forma 5-membered to 8-membered saturated or partially unsaturated ring whichin addition to the nitrogen atom which carries the groups R⁵ and R⁶ cancontain one or more further ring heteroatoms from the series N, O and Sand which can be substituted by one or more identical or differentsubstituents from the series fluorine, (C₁-C₅)-alkyl,hydroxy-(C₁-C₃)-alkyl-, —(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, aryl, CF₃, OH,—O—(C₁-C₇)-alkyl, —O-aryl, —O—(C₂-C₄)-alkyl-O—(C_(1-C) ₇)-alkyl,(C₂-C₃)-alkylenedioxy, NR⁷R⁸, CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N(C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)—NH₂,—S(O)_(n)—NH—(C₁-C₃)-alkyl, —S(O)_(n)—N((C₁-C₃)-alkyl)₂, oxo,—(CH₂)_(m)—NH₂, —(CH₂)_(m)—NH—(C₁-C₄)-alkyl and—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ where in the substituent-(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ the two alkyl groups can be connected by asingle bond and then together with the nitrogen atom carrying them forma 5-membered to 7-membered ring which besides that nitrogen atom and thecarbon atoms can additionally contain an oxygen atom, a sulfur atom or agroup NR⁵ as ring member;

R⁷ is hydrogen or (C₁-C₇)-alkyl which can be substituted by one or moreidentical or different substituents from the series OH,—O—(C₁-C₅)-alkyl, NH₂, —NH—(C₁-C₄) alkyl and —N((C₁-C₄)-alkyl)₂ where inthe substituent N((C₁-C₄)-alkyl)₂ the two alkyl groups can be connectedby a single bond and then together with the nitrogen atom carrying themform a 5-membered to 7-membered ring which besides that nitrogen atomand the carbon atoms can additionally contain an oxygen atom, a sulfuratom or a group NR⁵ as ring member;

R⁸ independently of R⁷ has one of the meanings of R⁷ or is—CO—(C₁-C₄)-alkyl;

“aryl” is phenyl, naphthyl or heteroaryl which can all be substituted byone or more identical or different substituent from the series halogen,(C₁-C₅)-alkyl, phenyl, tolyl, CF₃, —O—CF₃, NO₂, OH, —O—(C₁-C₅)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, (C₁-C₂)-alkylenedioxy, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —NH—CHO, —NH—CO—(C₁-C₅)-alkyl,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO, —CO—(C₁-C₅)-alkyl,—S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl and —S(O)_(n)-tolyl;

“heteroaryl” and “heteroarylene” are a residue of a monocyclic5-membered or 6-membered aromatic heterocycle or of a bicyclic8-membered to 10-membered aromatic heterocycle each of which containsone or more ring heteroatoms from the series N, O and S;

“heterocyclyl” is a residue of a monocyclic or polycyclic 5-membered to11-membered saturated or partially unsaturated heterocycle whichcontains one or more ring heteroatoms from the series N, O and S andwhich can be substituted by one or more identical or differentsubstituents from the series fluorine, (C₁-C₅)-alkyl, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —CN, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH and—CO—O—(C₁-C₅)-alkyl;

n is 0, 1 or 2;

m is 2, 3 or4;

X is O or NH or X is a nitrogen atom which via a single bond is attachedto a ring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ carrying the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ carrying itforms an anellated imidazole ring;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically acceptable salts;

where, however, the compound of formula I is excluded whereinsimultaneously the ring A² which comprises the carbon atoms which carrythe groups C(═X)—NH— and NH—SO₂R² is a benzene ring which is substitutedin positions 3 and 5 by chlorine, R² is methyl, X is oxygen andR¹—S(O)_(n)—A¹— is a 5-chloro-2-(4-chlorophenylmercapto)-phenyl residue.

If groups or substituents can occur several times in the compounds offormula I such as, for example R³, R⁴, R⁵, aryl, heterocyclyl, alkyl, orthe numbers n and m, they can all independently of one another have themeanings indicated and can in each case be identical or different.

Alkyl residues can be straight-chain or branched. This also applies whenthey are part of other groups, for example in alkoxy groups,alkoxycarbonyl groups or amino groups, or when they are substituted.Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, the n-isomersof these residues, isopropyl, isobutyl, isopentyl, sec-butyl,tert-butyl, neopentyl, 3,3-dimethylbutyl. The term alkyl here alsoexpressly includes unsaturated alkyl residues, I. e. alkyl residueswhich contain one or more double bonds and/or one or more triple bondssuch as, for example, alkenyl residues and alkinyl residues. Of course,an unsaturated alkyl group contains at least two carbon atoms. Specificalkyl groups whose number of carbon atoms can vary from 1 to a givenupper limit, thus also comprise unsaturated alkyl groups whose number ofcarbon atoms can vary from 2 to the given upper limit. Examples of suchresidues are the vinyl residue, the 1-propenyl residue, the 2-propenylresidue (allyl residue), the 2-butenyl residue, the 2-methyl-2-propenylresidue, the 3-methyl-2-butenyl residue, the ethinyl residue, the2-propinyl residue (propargyl residue), the 2-butinyl residue or the3-butinyl residue. Further, the term alkyl here also expressly includesalkyl residues in which by an internal ring closure within the alkylgroup a cyclic system is formed, i. e. the term alkyl also includessaturated and partially unsaturated cycloalkyl residues andcycloalkyl-alkyl- residues (alkyl substituted by cycloalkyl). Of course,a monocyclic cycloalkyl group contains at least three carbon atoms.

Specific alkyl groups whose number of carbon atoms can vary from 1 to agiven upper limit, thus also comprise monocyclic cycloalkyl groups whosenumber of carbon atoms can vary from 3 to the given upper limit, andappropriate cycloalkyl-alkyl- groups. Examples of such cycloalkylresidues are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl which can all also be substituted by one ormore identical or different (C₁-C₄)-alkyl residues, in particular bymethyl. Examples of such substituted cycloalkyl residues are4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclopentyl.Furthermore, unless stated otherwise the term alkyl here also expresslyincludes unsubstituted alkyl residues as well as alkyl residues whichare substituted by one or more, for example one, two, three or four,identical or different aryl residues. The term alkyl thus here alsoexpressly includes arylalkyl- residues such as, for example,aryl-(C₁-C₄)-alkyl-, for example benzyl residues, phenylethyl residuesor indanyl residues. In substituted alkyl residues, for examplearylalkyl-, hydroxyalkyl- such as —(C₁-C₃)-alkyl-OH or alkoxyalkyl- suchas —(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, the substituents can be present inany desired position.

A saturated or partially unsaturated 3-membered to 7-membered carbocyclerepresenting the ring A² can be derived from the monocyclic parentsystems cyclopropane, cyclobutane, cyclopentane, cyclohexane orcycloheptane. If the carbocycle is unsaturated it can contain, forexample, one double bond or, in the case of a 5-membered ring,6-membered ring or 7-membered ring, also two double bonds which can beisolated or conjugated. Double bonds can be present in any positionswith respect to the groups C(═X)—NH— and NH—SO₂—R², i.e., for example adouble bond can also be present between the two ring carbon atoms whichcarry these two groups.

Unless stated otherwise, phenyl residues, naphthyl residues andheterocyclic residues, for example heteroaryl residues, can beunsubstituted or can carry one or more, for example one, two, three orfour, identical or different substituents which can be in any desiredpositions. Unless stated otherwise, in these residues for example thosesubstituents can be present which are indicated as substituents of anaryl group. A preferred series of substituents that can be present inthe residue aryl is formed by the substituents halogen, (C₁-C₅)-alkyl,phenyl, tolyl, CF₃, NO₂, OH, —O—(C₁-C₅)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, (C₁-C₂)-alkylenedioxy, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —NH—CHO, —NH—CO—(C₁-C₅)-alkyl,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO, —CO—(C₁-C₅)-alkyl,—S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl and —S(O)_(n)-tolyl. If incompounds of the formula I nitro groups are present as substituents, intotal only up to two nitro groups can be present in the molecules. Ifphenyl residues, phenoxy residues, benzyl residues or benzyloxy residuesare present as substituents in, for example, aryl residues like phenylresidues and/or in heterocyclic residues then in these substituents thebenzene ring can also be unsubstituted or substituted by one or more,for example one, two, three or four, identical or different residues,for example by residues from the series (C₁-C₄)-alkyl, halogen, hydroxy,(C₁-C₄)-alkoxy, trifluoromethyl, cyano, hydroxycarbonyl,((C₁-C₄)-alkoxy)carbonyl, aminocarbonyl, nitro, amino,(C₁-C₄)-alkylamino, di-((C₁-C₄)-alkyl)amino and((C₁-C₄)-alkyl)carbonylamino.

In monosubstituted phenyl residues the substituent can be in the2-position, the 3-position or the 4-position, in disubstituted phenylresidues the substituents can be in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. Intrisubstituted phenyl residues the substituents can be in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position or 3,4,5-position. Tolyl (i.e., methylphenyl) can be2-tolyl, 3-tolyl or 4-tolyl. Naphthyl can 1-naphthyl or 2-naphthyl. Inmonosubstituted 1-naphthyl residues the substituent can be in the2-position, the 3-position, the 4-position, the 5-position, the6-position, the 7-position or the 8-position, in monosubstituted2-naphthyl residues in the 1-position, the 3-position, the 4-position,the 5-position, the 6-position, the 7-position or the 8-position.

The above explanations as well as the following explanations relating tomonovalent residues correspondingly apply to the divalent residuesphenylene, naphthylene and heteroarylene. The free bonds via which thedivalent residues are attached to the adjacent groups can be present onany ring carbon atoms. In the case of a phenylene residue they can be in1,2-position (ortho-phenylene), 1,3-position (meta-phenylene) or1,4-position (para-phenylene). In the case of a naphthylene residue thefree bonds can be in 1,2-position (=1,2-naphthylene or1,2-naphthalinediyl) or in 1,3-position, 1,4-position, 1,5-position,1,6-position, 1,7-position, 1,8-position, 2,3-position, 2,6-position or2,7-position. In the case of 5-membered ring aromatics containing oneheteroatom such as, for example, thiophene or furan, the two free bondscan be in 2,3-position, 2,4-position, 2,5-position or 3,4-position. Adivalent residue derived from pyridine can be a 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-pyridinediyl residue. In the case of unsymmetrical divalentresidues the present invention includes all positional isomers, i.e., inthe case of a 2,3-pyridinediyl residue, for example, it includes thecompound in which the one adjacent group is present in the 2-positionand the other adjacent group is present in the 3-position as well as thecompound in which the one adjacent group is present in the 3-positionand the other adjacent group is present in the 2-position.

Heteroaryl residues, heteroarylene residues, heterocyclyl residues,heterocycles representing the ring A² and rings which are formed by twogroups bonded to a nitrogen atom together with this nitrogen atom arepreferably derived from heterocycles which contain one, two, three orfour identical or different ring heteroatoms, more preferably fromheterocycles which contain one, two or three, in particular one or two,identical or different heteroatoms. Unless stated otherwise, theheterocycles can be monocyclic or polycyclic, for example monocyclic,bicyclic or tricyclic. Preferably they are monocyclic or bicyclic. Therings preferably are 5-membered rings, 6-membered ring or 7-memberedring. Examples of monocyclic and bicyclic heterocyclic systems fromwhich residues occurring in the compounds of the formula I can bederived, are pyrrole, furan, thiophene, imidazole, pyrazole,1,2,3-triazole, 1,2,4-triazole, 1,3-dioxole, 1,3-oxazole (=oxazole),,1,2-oxazole (=isoxazole), 1,3-thiazole (=thiazole), 1,2-thiazole(=isothiazole), tetrazole, pyridine, pyridazine, pyrimidine, pyrazine,pyran, thiopyran, 1,4-dioxine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine,1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, 1,2,4,5-tetrazine, azepine,1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,3-oxazepine,1,3-thiazepine, indole, benzothiophene, benzofuran, benzothiazole,benzimidazole, quinoline, isoquinoline, cinnoline, quinazoline,quinoxaline, phthalazine, thienothiophenes, 1,8-naphthyridine and othernaphthyridines, pteridin, or phenothiazine, each of them in saturatedform (perhydro form) or in partially unsaturated form (for example inthe dihydro form or the tetrahydro form) or in maximally unsaturatedform, insofar as the respective forms are known and stable.

Thus, the heterocycles which are suitable also include, for example, thesaturated heterocycles pyrrolidine, piperidine, piperazine, morpholineand thiomorpholine. The degree of saturation of heterocyclic groups isindicated in their individual definitions. Unsaturated heterocycles cancontain, for example, one, two or three double bonds within the ringsystem. 5-membered rings and 6-membered rings can in particular also bearomatic.

The residues derived from these heterocycles can be attached via anysuitable carbon atom. Nitrogen heterocycles which can carry a hydrogenatom or a substituent on a ring nitrogen atom, for example pyrrole,imidazole, pyrrolidine, morpholine, piperazine etc., can also beattached via a ring nitrogen atom, in particular if the heterocyclicresidue in question is bonded to a carbon atom. For example, a thienylresidue can be present as 2-thienyl residue or 3-thienyl residue, afuryl residue as 2-furyl residue or 3-furyl residue, a pyridyl residueas 2-pyridyl residue, 3-pyridyl residue or 4-pyridyl residue, apiperidinyl residue as 1-piperidinyl residue (i.e., piperidino residue),2-piperidinyl residue, 3-piperidinyl residue or 4-piperidinyl residue, a(thio)morpholinyl residue as 2-(thio)morpholinyl residue,3-(thio)morpholinyl residue or 4-(thio)morpholinyl residue (i.e.,thiomorpholino residue). A residue derived from 1,3-thiazole orimidazole which is attached via a carbon atom can be attached via the2-position, the 4-position or the 5-position.

Unless stated otherwise the heterocyclic groups can be unsubstituted orcan carry one or more, for example one, two, three, or four, identicalor different substituents. Substituents in heterocycles can be presentin any desired positions, for example in a 2-thienyl residue or 2-furylresidue in the 3-position and/or in the 4-position and/or in the5-position, in a 3-thienyl residue or 3-furyl residue in the 2-positionand/or in the 4-position and/or in the 5-position, in a 2-pyridylresidue in the 3-position and/or in the 4-position and/or in the5-position and/or in the 6-position, in a 3-pyridyl residue in the2-position and/or in the 4-position and/or in the 5-position and/or inthe 6-position, in a 4-pyridyl residue in the 2-position and/or in the3-position and/or in the 5-position and/or in the 6-position. Unlessstated otherwise, for example those substituents can be present assubstituents in heterocyclic groups which are indicated in thedefinition of the group aryl, and in the case of saturated and partiallyunsaturated heterocycles as further substituents also the oxo group andthe thioxo group can be present. Substituents on a heterocycle as wellas substituents on a carbocycle can also form a ring, i.e., to a ringsystem further rings can be condensed (or anellated) so that, forexample, also cyclopenta-condensed, cyclohexa-condensed orbenzo-condensed rings can be present. Suitable substituents on asubstitutable ring nitrogen atom of a heterocycle are in particular, forexample, unsubstituted (C₁-C₅)-alkyl residues and aryl-substituted alkylresidues, aryl residues, acyl residues such as —CO—(C₁-C₅)-alkyl, orsulfonyl residues such as —SO₂—(C₁-C₅)-alkyl. Suitable nitrogenheterocycles can also be present as N-oxides or as quaternary saltscontaining a counterion which is derived from a physiologicallyacceptable acid. Pyridyl residues, for example, can be present aspyridine-N-oxides.

“Halogen” is fluorine, chlorine, bromine or iodine, and preferablyfluorine or chlorine.

Without limiting the present invention, in the formulae Ia, Ib, Ic, Id,Ie, If, Ig and Ih examples of groups of compounds of the invention areshown in which A² in the formula I has specific denotations. A¹, R¹, R²,R³, X and n in the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih aredefined as above for the formula I, and the number k in the formula Ibis 1, 2, 3, 4 or 5, in particular 3 or 4.

On the benzene ring depicted in formula Ia which carries the groupsC(═X)—NH— and —NHSO₂R², four positions are present which can carry aresidue R³. The compounds of formula Ia can thus carry four residues R³which, independently of one another, can all be hydrogen or can have ameaning different from hydrogen, i.e., in the compounds of formula Iathe benzene ring depicted in formula Ia can be unsubstituted or cancarry one, two, three or four identical or different substituents fromthe series halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl and (C₁-C₅)-alkyl which can be substituted byone or more identical or different residues R⁴. These explanationsaccordingly also apply to the compounds of formulae Ib to Ih.

The compounds of the formula I wherein X is a nitrogen atom which via asingle bond is attached to a ring carbon atom in the group A¹ which ringcarbon atom is directly adjacent to the carbon atom in A¹ carrying thegroup —NH—C(═X)— so that the group —NH—C(═X)— together with the carbonatoms in A¹ carrying it forms an anellated imidazole rin(g, arerepresented by the formula Ii.

A², R¹, R¹, R³ and nin the formula Ii are defined as above for theformula I. The ring A³ which has resulted from the group A¹ by theformation of a bond to the nitrogen atom representing X and which ringcomprises the two carbon atoms depicted in formula Ii carrying thenitrogen atoms of the anellated imidazole ring, is a benzene ring, anaphthalene ring or a heteroaromatic ring, where to these rings theabove explanations relating to A¹ correspondingly apply.

The present invention includes all stereoisomeric forms of the compoundsof the formula I. Centers of asymmetry that are present in the compoundsof formula I can all independently of one another have S configurationor R configuration. The invention includes all possible enantiomers anddiastereomers and mixtures of two or more stereoisomers, for examplemixtures of enantiomers and/or diastereomers, in all ratios. Thus,enantiomers are a subject of the invention in enantiomerically pureform, both as levorotatory and as dextrorotatory antipodes, in the formof racemates and in the form of mixtures of the two enantiomers in allratios. In the case of a cis/trans isomerism the invention includes boththe cis form and the trans form as well as mixtures of these forms inall ratios. The preparation of individual stereoisomers can be carriedout, if desired, by separation of a mixture by customary methods, forexample by chromatography or crystallization, by the use ofstereochemically uniform starting materials for the synthesis or bystereoselective synthesis. Optionally a derivatization can be carriedout before a separation of stereoisomers. The separation of a mixture ofstereoisomers can be carried out at the stage of the compounds of theformula I or at the stage of an intermediate during the synthesis. Thepresent invention also includes all tautomeric forms of the compounds offormula I.

If the compounds of the formula I contain one or more acidic or basicgroups the invention also includes the corresponding physiologically ortoxicologically acceptable salts, in particular the pharmaceuticallyutilizable salts. Thus, the compounds of the formula I which containacidic groups can be present on these groups and can be used accordingto the invention, for example, as alkali metal salts, alkaline earthmetal salts or as ammonium salts. Examples of such salts are sodiumsalts, potassium salts, calcium salts, magnesium salts or salts withammonia or organic amines such as, for example, ethylamine,ethanolamine, triethanolamine or amino acids. Compounds of the formula Iwhich contain one or more basic groups, i.e. groups which can beprotonated, can be present and can be used according to the invention inthe form of their acid addition salts with inorganic or organic acids,for example as salts with hydrogen chloride, hydrogen bromide,phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, etc. If the compounds ofthe formula I simultaneously contain acidic and basic groups in themolecule the invention also includes, in addition to the salt formsmentioned, inner salts or betaines (zwitterions). Salts can be obtainedfrom the compounds of the formula I by customary methods which are knownto the person skilled in the art, for example by combination with anorganic or inorganic acid or base in a solvent or dispersant, or byanion exchange or cation exchange from other salts. The presentinvention also includes all salts of the compounds of the formula Iwhich, owing to low physiological compatibility, are not directlysuitable for use in pharmaceuticals but which can be used, for example,as intermediates for chemical reactions or for the preparation ofphysiologically acceptable salts.

The present invention furthermore includes all solvates of compounds ofthe formula I, for example hydrates or adducts with alcohols, and alsoderivatives of the compounds of the formula I such as, for exampleesters, amides, prodrugs and active metabolites.

A¹ preferably is a phenylene residue or a 5-membered or 6-memberedheteroarylene residue, more preferably phenylene, where all theseresidues can be unsubstituted or can be substituted as indicated. If thegroup A¹ is substituted, I. e. if it carries one or more furthersubstituents in addition to the group R¹—S(O)_(n), it is preferablysubstituted by one or two identical or different of the substituentsindicated above. Preferably a phenylene residue representing A¹ isunsubstituted, I. e. besides the groups R¹—S(O)_(n) and C(═X)—NH itcarries four hydrogen atoms. The group R¹—S(O)_(n) is preferablyattached to a carbon atom in A¹ which is not directly adjacent to thecarbon atom which carries the group C(═X)—NH. If A¹ is phenylene thegroup R¹—S(O)_(n) is particularly preferably located in the metaposition or in the para position, more particularly preferably in thepara position, with respect to the carbon atom which carries the groupC(═X)—NH.

The ring A² which comprises the two carbon atoms which carry the groupsR²—SO₂—NH and C(═X)—NH— preferably is an aromatic ring, more preferablya benzene ring or a thiophene ring, particularly preferably a benzenering, where all these rings can be unsubstituteci or substituted by oneore more residues R³ which are different from hydrogen.

R¹ preferably is (C₁-C₇)-alkyl, NR⁵R⁶ or aryl, more preferably NR⁵R⁶,phenyl or 5-membered or 6-membered heteroaryl, particularly preferablyNR⁵R⁶, where all these residues can be unsubstituted or substituted asindicated and where, as stated above, R¹ can be NR⁵R⁶ if the number n inthe group R¹—S(O)_(n)— is 2.

R² preferably is aryl, more preferably phenyl or 5-membered or6-membered heteroaryl, particularly preferably phenyl or a residue of amonocyclic 5-membered or 6-membered aromatic heterocycle which containsone or two identical or different heteroatoms from the series N, O and Ssuch as, for example, phenyl, thienyl, pyrazolyl, imidazolyl,isoxazolyl, thiazolyl, pyridyl etc., in particular phenyl or 2-thienyl,where all these residues can be unsubstituted or substituted asindicated. Preferably an aryl residue representing R² is substituted. Ifan aryl residue representing R² is substituted it is preferablysubstituted by one, two or three, in particular by one or two, identicalor different substituents. Substituents in an aryl residue representingR² preferably are substituents from the series halogen, CF₃, —O—CF₃,NO₂, —CN, (C₁-C₄)-alkyl and —O—(C₁-C₄)-alkyl, more preferablysubstituents from the series F, Cl, Br, CF₃, —O—CF₃, NO₂, —CN, CH₃ and—OCH₃. Especially preferably a substituted aryl residue representing R²is substituted by Cl, for example by one or two, in particular one,chlorine atoms.

The rings representing A² can be unsubstituted or substituted asindicated. When they are unsubstituted they only carry residues R³ whichare hydrogen. When they are substituted they carry one or more residuesR³ which are different from hydrogen. Those substituent positions whichdo not carry a residue R³ which is different from hydrogen, carryhydrogen atoms. If the ring A² carries one or more residues R³ which aredifferent from hydrogen it preferably carries one or two such residuesR³, in particular one such residue R³. Residues R³ which are differentfrom hydrogen are preferably located in positions of the ring A² whichare not directly adjacent to the groups C(═X)—NH and R²—SO₂—NH. If A² isa saturated or partially unsaturated carbocycle, residues R³ which aredifferent from hydrogen preferably are (C₁-C₄)-alkyl, in particularmethyl. If A² is an aromatic ring, in particular if A² is a benzenering, residues R³ which are different from hydrogen preferably are(C₁-C₃)-alkyl, halogen, (C₁-C₃)-alkoxy or CF₃, more preferably methyl,chlorine or methoxy. If a A² is an aromatic ring, in particular abenzene ring, it is very particularly preferred if the ring carries onechlorine atom or two methoxy groups as substituents, I. e., if oneresidue R³ is present which is chlorine or if two residues R³ arepresent which are methoxy, and the other positions on the benzene ringcarry hydrogen atoms. If A² is a benzene ring residues R³ which aredifferent from hydrogen are preferably located in positions 4 and/or 5(with respect to the group C(═X)—NH in the 1-position and the groupR²—SO₂—NH in the 2-position).

If a group is substituted by one or more residues R⁴ it is preferablysubstituted by one, two or three, in particular one or two, identical ordifferent residues R⁴. R⁴ preferably is hydroxy, (C₁-C₄)-alkyloxy,di-((C₁-C₄)-alkyl)amino or heteroaryl.

R⁵ and R⁶ preferably are independently of one another hydrogen,(C₁-C₉)-alkyl, (C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl- or 5-membered or6-membered aryl or together with the nitrogen atom carrying R⁵ and R⁶form a 5-membered to 7-membered heterocycle which in addition to thenitrogen atom carrying the groups R⁵ and R⁶ can contain one further ringheteroatom from the series N, O and S and which can be substituted byone or more, for example one, two, three or four, identical or differentresidues from the series (C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl-,5-membered or 6-membered aryl, carbamoyl, hydroxy and oxo. It isparticularly preferred if R⁵ and R⁶ together with the nitrogen atomcarrying these residues form a 5-membered, 6-membered or 7-memberedheterocycle which in addition to the nitrogen atom carrying the groupsR⁵ and R⁶ can contain one further ring heteroatom from the series N, Oand S and which can be substituted by one or more, for example one, two,three or four, identical or different residues from the series(C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl-, 5-membered or 6-membered aryl,carbamoyl, hydroxy and oxo, in particular (C₁-C₃)-alkyl such as, forexample, methyl. Preferably a heterocycle which is formed from thegroups R⁵ and R⁶ together with the nitrogen atom carrying these residuesis saturated.

An especially preferable heterocycle which is formed by R⁵ and R⁶together with the nitrogen atom carrying these residues, is derived frommorpholine, thiomorpholine, 1,1-dioxo-thiomorpholine,1-oxo-thiomorpholine, from dialkylmorpholines such asdimethylmorpholines, from 2,6-dimethylmorpholine,cis-2,6-dimethylmorpholine, 3,5-dimethylmorpholine,cis-3,5-dimethylmorpholine, 1-(pyrimidin-2-yl)-piperazine,piperidine-4-carboxamide, 1-(2-hydroxyethyl)-piperazine,1-methylpiperazine, 1-ethylpiperazine, from 1-arylpiperazines, fromethyl piperazine-1-carboxylate, piperidine, 2-methylpiperidine,2,6-dimethylpiperidine, cis-2,6-dimethylpiperidine,3,5dimethylpiperidine, cis-3,5-dimethylpiperidine, 4-hydroxypiperidine,from 4-oxopiperidine or a ketal thereof like1,4-dioxa-8-aza-spiro[4.5]decan, from tetrahydropyridine,tetrahydropyrimidine, 1-methylhomopiperazine, thiazolidine, pyrroline,pyrrolidine, 3-hydroxypyrrolidine, 1,2,3,4-tetrahydroisoquinoline or2,3-dihydro-1H-isoindole, where these rings are attached via the ringnitrogen atom or, in the case of piperazine derivatives, via theunsubstituted ring nitrogen atom. A more especially preferableheterocycle which is formed by R⁵ and R⁶ together with the nitrogen atomcarrying these residues, is derived from morpholine, thiomorpholine,1,1-dioxo-thiomorpholine, 1-oxo-thiomorpholine, 2,6-dimethylmorpholine,cis-2,6-dimethylmorpholine, 3,5-dimethylmorpholine,cis-3,5-dimethylmorpholine, 1-(pyrimidin-2-yl)-piperazine,piperidine-4-carboxamide, 1,2,3,4-tetrahydroisoquinoline or2,3-dihydro-1H-isoindole, moreover preferably from morpholine,2,6-dimethylmorpholine or cis-2,6-dimethylmorpholine, in particular frommorpholine or cis-2,6-dimethylmorpholine, where these rings are attachedvia the ring nitrogen atom or, in the case of the piperazine derivative,via the unsubstituted ring nitrogen atom.

R⁷ preferably is hydrogen, (C₁-C₃)-alkyl,((C₁-C₄)-alkyl)₂N—(C₁-C₃)-alkyl- or (C₁C₄)-alkyl-O—(C₁-C₃)-alkyl-.

R⁸ preferably is hydrogen, (C₁-C₃)-alkyl or acetyl.

Aryl preferably is phenyl or heteroaryl, in particular phenyl or5-membered or 6-membered heteroaryl. Unless stated otherwise, preferredsubstituents on aryl residues are halogen, CF₃, (C₁-C₃)-alkyl, cyano,nitro and (C₁-C₃)-alkyloxy, more preferred substituents are CF₃,chlorine, methyl and methoxy.

Heteroaryl and heteroarylene preferably are a residue of a monocyclic5-membered or 6-membered aromatic heterocycle, in particular a residuederived from the heteroaromatics thiophene, pyrazole, thiazole, oxazole,isoxazole, pyridine, pyrimidine, pyridazine and tetrazole.

Heterocyclyl preferably is a residue derived from a saturatedheterocycle, more preferably a residue of a monocyclic 5-membered or6-membered saturated heterocycle, in particular a residue which isderived from pyrrolidine, piperidine, from N-alkylpiperazines, frommorpholine, from dialkylmorpholines, from thiomorpholine ortetrahydrofuran. In addition, the above explanations on preferredheterocycles which are formed by the residues R⁵ and R⁶ together withthe nitrogen atom carrying these residues correspondingly apply toheterocyclyl residues which are attached via a ring nitrogen atom.

If a group S(O)_(n) is bonded to a nitrogen atom the number n thereinpreferably is 1 or 2, more preferably 2. The number n in the groupR¹—S(O)_(n) preferably is 0 or 2, particularly preferably 2.

X preferably is O or a nitrogen atom which via a single bond is attachedto a ring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ carrying the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ carrying itforms an anellated imidazole ring. Particularly preferably X is O.

Preferred compounds of the formula I are those compounds in which one ormore of the residues contained therein have preferred meanings, allcombinations of preferred substituent definitions being a subject of thepresent invention. Also with respect to all preferred compounds of theformula I the present invention includes all stereoisomeric forms andmixtures thereof in all ratios, and their physiologically acceptablesalts. Groups of preferred compounds are also formed, for example, bythe compounds of the formulae Ia, Ib, Ic, Id, Ie, If, Ig and Ih in whichone or more residues have preferred meanings, in all theirstereoisomeric forms and mixtures thereof in all ratios, and theirphysiologically acceptable salts.

A group of particularly preferred compounds is formed, for example, bycompounds of the formula I in which

A¹ is phenylene or heteroarylene where these residues can beunsubstituted or substituted by one or more identical or differentsubstituents from the series halogen, (C₁-C₄)-alkyl, CF₃,—O—(C₁-C₄)-alkyl and —CN;

the ring A² which comprises the two carbon atoms which carry the groupsR²—SO₂—NH and C(═X)—NH— is an aromatic ring;

R¹ is (C₁-C₇)-alkyl which can be substituted by one or more identical ordifferent residues R⁴, or is aryl, or if the number n in the groupR¹—S(O)_(n)— is 2 also is NR⁵R⁶;

R² is aryl;

R³ denotes one or more identical or different residues from the serieshydrogen, halogen, CF₃, OH, —O—(C₁-C₄)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₄)-alkyl, —O-aryl, NO₂, —CN, NR⁷R⁸, —CO—NR⁷R⁸,—CO—OH, —CO—O—(C₁-C₄)-alkyl, heterocyclyl, —S(O)_(n)—(C₁-C₄)-alkyl and(C₁-C₄)-alkyl which can be substituted by one or more identical ordifferent residues R⁴;

R⁴ is fluorine, OH, —O—(C₁-C₁₀)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl,—O-aryl, —CN, NR⁷R⁸, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alky)₂, —CO—OH, —CO—O—(C₁-C₄)-alkyl, heterocyclyl or oxo;

R⁵ and R⁶ independently of one another are hydrogen, (C₁-C₉)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl- or aryl or together with the nitrogenatom carrying R⁵ and R⁶ form a 5-membered to 7-membered heterocyclewhich in addition to the nitrogen atom carrying the groups R⁵ and R⁶ cancontain one further ring heteroatom from the series N, O and S and whichcan be substituted by one or more identical or different residues fromthe series (C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl-, aryl, carbamoyl,hydroxy and oxo;

R⁷ is hydrogen, (C₁-C₃)-alkyl, ((C₁-C₄)-alkyl)₂N—(C₁-C₃)-alkyl- or(C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl-;

R⁸ is hydrogen, (C₁-C₃)-alkyl or acetyl;

“aryl” is phenyl or heteroaryl which can all be substituted by one ormore identical or different substituents from the series halogen,(C₁-C₄)-alkyl, phenyl, CF₃, NO₂, —O—(C₁-C₄)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—CO—(C₁-C₄)-alkyl, —CN, —CO—NH₂, —CO—OHand —CO—O—(C₁-C₄)-alkyl;

heteroaryl and heteroarylene are a residue of a monocyclic 5-membered or6-membered aromatic heterocycle which contains one or more identical ordifferent ring heteroatoms from the series N, O and S;

heterocyclyl is a residue of a monocyclic 5-membered or 6-memberedsaturated heterocycle which contains one or more identical or differentring heteroatoms from the series N, O and S and which can be substitutedby one or more identical or different substituents from the seriesfluorine, (C₁-C₄)-alkyl, OH, —O—(C₁-C₄)-alkyl, NH₂, —CN, —CO—NH₂, —CO—OHand —CO—O—(C₁-C₄)-alkyl;

n is 0, 1 or 2;

X is oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically acceptable salts.

A group of more particularly preferred compounds is formed, for example,by compounds of the formula I in which:

A¹ is phenylene which is unsubstituted or substituted by one or moreidentical or different substituents from the series halogen,(C₁-C₄)-alkyl, CF₃, —O—(C₁-C₄)-alkyl and —CN;

the ring A² which comprises the two carbon atoms which carry the groupsR²—SO₂—NH and C(═X)—NH— is a benzene ring;

R¹ is NR⁵R⁶;

R² is aryl;

R³ denotes one or more identical or different residues from the serieshydrogen, halogen, CF₃, —O—(C₁-C₄)-alkyl, —CN and (C₁-C₄)-alkyl;

R⁵ and R ⁶ together with the nitrogen atom carrying R⁵ and R⁶ form a5-membered or 6-membered saturated heterocycle which in addition to thenitrogen atom carrying the groups R ⁵and R⁶ can contain one further ringheteroatom from the series N, O and S and which can be substituted byone or more identical or different residues from the series(C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl-, aryl, carbamoyl, hydroxy and oxo;

aryl is phenyl or 5-membered or 6-membered heteroaryl containing one ormore identical or different ring heteroatoms from the series N, O and Swhich residues can all be substituted by one or more identical ordifferent substituents from the series halogen, (C₁-C₄)-alkyl, CF₃, NO₂,—O—(C₁-C₄)-alkyl, —NH—CO—(C₁-C₄)-alkyl and —CN;

n is 2;

X is oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically acceptable salts.

A group of especially preferred compounds is formed, for example, bycompounds of the formula I in which:

A¹ is an unsubstituted divalent phenylene residue;

the ring A² which comprises the two carbon atoms which carry the groupsR²—SO₂—NH and C(═X)—NH— is a benzene ring;

R¹ is NR ⁵R⁶;

R² is aryl;

R³ denotes one or more identical or different residues from the serieshydrogen, halogen, —O—(C₁-C₄)-alkyl and (C₁-C₄)-alkyl;

R⁵ and R⁶ together with the nitrogen atom carrying R⁵ and R⁶ form asaturated 6-membered heterocycle which in addition to the nitrogen atomcarrying the groups R⁵ and R⁶ can contain one further ring heteroatomfrom the series N, O and S and which can be substituted by one or moreidentical or different residues from the series (C₁-C₃)-alkyl, aryl, oxoand carbamoyl;

aryl is phenyl or 5-membered or 6-membered heteroaryl containing one ormore identical or different ring heteroatoms from the series N, O and Swhich residues can all be substituted by one or more identical ordifferent substituents from the series halogen, (C₁-C₄)-alkyl, CF₃ and—O—(C₁-C₄)-alkyl;

n is 2;

X is oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically acceptable salts.

A group of even more preferred compounds is formed, for example, bycompounds of the formula I in which:

A¹ is an unsubstituted divalent 1,4-phenylene residue;

the ring A² which comprises the two carbon atoms which carry the groupsR²—SO₂—NH and C(═X)—NH—, together with the residues R³, is a benzenering which carries one or two substituents from the series chlorine andmethoxy;

R¹ is NR⁵R⁶;

R² is phenyl or thienyl which residues are all substituted by one or twochlorine atoms;

R⁵ and R⁶ together with the nitrogen atom carrying R⁵ and R⁶ form asaturated 6-membered heterocycle which in addition to the nitrogen atomcarrying the groups R⁵ and R⁶ can contain one further ring heteroatomfrom the series O and S and which is unsubstituted or substituted by oneor two methyl residues;

n is 2;

X is oxygen;

in all their stereoisomeric forms and mixtures thereof in all ratios,and their physiologically acceptable salts.

The presents invention also relates to processes for the preparation ofthe compounds of the formula I which are described in the following andby which the compounds of the invention are obtainable. According toScheme 1 compounds of the invention can be obtained, for example, byfirst reacting an aminocarboxylic acid of the formula II with a sulfonylchloride of the formula R²—SO₂—Cl or a sulfonic acid anhydride in thepresence of a base in a solvent like water, pyridine or an ether.Suitable bases are inorganic bases like sodium carbonate or organicbases like, for example, pyridine or triethylamine. Thesulfonylaminocarboxylic acid of the formula III that is obtained canthen be activated, for example by reaction with a chlorinating agentlike phosphorus pentachloride, phosphorus oxychloride or thionylchloride in an inert solvent, to give an acid chloride of the formula IVwhich is then reacted with an arylamine.

The activation of the carboxylic acid group in the compounds of theformula III can, however, also be carried out in a different manner, forexample by one of the numerous methods for the formation of amide bondsin peptide chemistry which are well-known to the skilled person, forexample by conversion into a mixed anhydride or an activated ester or byusing a carbodiimide like dicyclohexylcarbodimide.

The reaction of the activated sulfonylaminocarboxylic acid with anarylamine is favorably carried out in an inert solvent such as, forexample, pyridine, tetrahydrofuran or toluene in the absence or in thepresence of an inert auxiliary base like, for example, a tertiary amineor pyridine. If the arylamine that is employed in the reaction with theactivated carboxylic acid already contains the desired substituentR¹—S(O)_(n) then the reaction directly provides the final compound ofthe formula I. Compounds of the formula I in which the number n in thegroup R¹—S(O)_(n) is 1 or 2 can also be obtained by reacting anactivated carboxylic acid with a mercapto substituted arylamine of theformula R¹—S—A¹—NH₂ and then oxidizing the mercapto group in thecompound of the formula V under standard conditions, for example with aperoxide like hydrogen peroxide or a peracid like 3-chloroperbenzoicacid or monoperoxyphthalic acid in a solvent like, for example,methylene chloride or acetone. The activated carboxylic acids can alsofirst be reacted with arylamines of the formula A¹—NH₂. The resultingreaction product of the formula VI can then be chlorosulfonated understandard conditions and the chlorosulfonyl group can then be convertedunder standard conditions into the group R¹—SO₂, for example by reactionwith suitable amines in substance or in a solvent likeN-methylpyrrolidone, dimethylformamide, toluene or an ether, optionallyin the presence of an auxiliary base. In a similar manner the activatedcarboxylic acids can be reacted with fluorosulfonylarylamines of theformula F—SO₂—A¹—NH₂ and the fluorosulfonyl intermediates of the formulaVII that are obtained can be converted under standard conditions intothe compounds of the formula I according to the invention.

The compounds of the formula I according to the invention canfurthermore be obtained by reacting the activatedsulfonylaminocarboxylic acids, for example the acid chlorides of theformula IV shown in Scheme 1, with a mercaptoarylamine of the formulaH₂N—A¹—SH which is unsubstituted on the sulfur atom. In a nucleophilicsubstitution reaction the product of the formula VIII that is obtainedcan subsequently be alkylated or arylated on the sulfur atom with analkyl halogenide or an aryl halogenide or another reactive compoundunder standard conditions and, if desired, be oxidized on the sulfur togive the sulfoxide or the sulfone as explained above with respect to thecompounds of the formula V (see Scheme 2).

Compounds of the formula I can also be obtained, for example, by firstactivating a suitably substituted nitrocarboxylic acid of the formulaIX, for example by converting it into the respective acid chloride ofthe formula X or by another procedure, and then reacting it with asubstituted arylamine of the formula R¹—S(O)_(n)—A¹—NH₂ analogously tothe procedures described above (see Scheme 3). Here, too, as arylaminesfluorosulfonylarylamines of the formula F—SO₂—A¹—NH₂ can be employed,and in the N-(fluorosulfonylaryl)-carboxamides of the formula XI thatare obtained the fluorosulfonyl group can be converted under standardconditions into a group R¹—SO₂ according to the invention, for examplewith an amine of the formula HNR⁵R⁶.

Before the nitro group is reduced to an amino group, in the nitrointermediates of the formula XII, use can be made of the activatingeffect of the nitro group on the ring A² and a suitable residue R³, forexample a halogen atom, can be replaced with a different residue R³ byreaction with a nucleophile, for example an amine. The reduction of thenitro group to give an amino group can, for example, be carried out bycatalytic hydrogenation in the presence of a noble metal catalyst or,preferably, in the presence of Raney nickel in a solvent like ethanol,glacial acetic acid or an ethanolic solution of hydrogen chloride, or itcan be carried out by reduction with a base metal like zinc, tin or ironin the presence of an acid. The reduction can also be carried out, forexample, with tin(II) chloride or by reaction with sodium dithionite,favorably in a mixture of methanol, tetrahydrofuran and water assolvent. The sulfonylation of the amino group in the reduction productof the formula XIII with an activated sulfonic acid derivative can becarried out analogously to the reactions described above, for examplewith a sulfonic acid chloride in pyridine, and finally gives thecompound of the formula I.

The compounds of the formula I in which X is a nitrogen atom which via asingle bond is attached to a ring carbon atom in the group A¹ which ringcarbon atom is directly adjacent to the carbon atom in A¹ carrying thegroup —NH—C(═X)—, I. e. the benzimidazole derivatives of the formula Ii,can for example be obtained by reacting an activatedsulfonylaminocarboxylic acid derivative obtained as described aboveaccording to Scheme 1, for example a carboxylic acid chloride of theformula IV, (or also, in analogy to Scheme 3, a nitrocarboxylic acidderivative) with a 1,2-diaminoarene in the presence of a dehydratingagent such as, for example, thionyl chloride or phosphorus pentachloride(see Scheme 4). The reaction is usually carried out in an inert solvent,for example in a hydrocarbon like toluene or xylene. The1,2-diaminoarene can already contain the final group R¹—S(O)_(n) or aprecursor group thereof, for example the group R¹—S. Subsequent steps,for example reactions on the sulfur atom, can then be carried out asexplained above. Just so, unsubstituted 1,2-diaminoarenes can beemployed and the resulting products of the formula XIV can bechlorosulfonated, for example with chlorosulfuric acid, and the sulfonylchlorides that are obtained can be converted into the final compoundscontaining the group R¹—SO₂, for example by reaction with a suitableamine.

All reactions for the synthesis of the compounds of the formula I areper se well-known to the skilled person and can be carried out understandard conditions according to or analogously to procedures describedin the literature, for example in Houben-Weyl, Methoden der OrganischenChemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart, orOrganic Reactions, John Wiley & Sons, New York. Depending on thecircumstances of the individual case, in order to avoid side reactionsduring the synthesis of a compound of the formula I it can be necessaryor advantageous to temporarily block functional groups by introducingprotective groups and to deprotect them in a later stage of thesynthesis, or introduce functional groups in the form of precursorgroups which in a later reaction step are converted into the desiredfunctional groups. Such synthetic strategies and protective groups andprecursor groups which are suitable in an individual case are known tothe skilled person. If desired the compounds of the formula I can bepurified by customary purification procedures, for example byrecrystallization or chromatography. The starting compounds for thepreparation of the compounds of the formula I are commercially availableor can be prepared according to or analogously to literature procedures.

The compounds of the formula I according to the invention effect anincrease of the cGMP concentration via the activation of the solubleguanylate cyclase (sGC), and they are therefore useful agents for thetherapy and prophylaxis of disorders which are associated with a low ordecreased cGMP level or which are caused thereby, or for whose therapyor prophylaxis an increase of the present cGMP level is desired. Theactivation of the sGC by the compounds of the formula I can be examined,for example, in the activity assay described below.

Disorders and pathological conditions which are associated with a lowcGMP level or in which an increase of the cGMP level is desired and forwhose therapy and prophylaxis it is possible to use compounds of theformula I are, for example, cardiovascular diseases, such as endothelialdysfunction, diastolic dysfunction, atherosclerosis, hypertension,stable and unstable angina pectoris, thromboses, restenoses, myocardialinfarction, strokes, cardiac insufficiency or pulmonary hypertonia, or,for example, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency and diabetes. Compounds of the formula I can additionallybe used in the therapy of cirrhosis of the liver and also for improvinga restricted memory performance or ability to learn.

The compounds of the formula I and their physiologically acceptablesalts can be administered to animals, preferably to mammals, and inparticular to humans, as pharmaceuticals by themselves, in mixtures withone another or in the form of pharmaceutical preparations. A subject ofthe present invention therefore also are the compounds of the formula Iand their physiologically acceptable salts for use as pharmaceuticals,their use for activating soluble guanylate cyclase, for normalizing adisturbed cGMP balance and in particular their use in the therapy andprophylaxis of the abovementioned syndromes as well as their use forpreparing medicaments for these purposes.

Furthermore, a subject of the present invention are pharmaceuticalpreparations (or pharmaceutical compositions) which comprise as activecomponent an effective dose of at least one compound of the formula Iand/or a physiologically acceptable salt thereof and a customarypharmaceutically acceptable carrier, I. e. one or more pharmaceuticallyacceptable carrier substances and/or additives. A subject of the presentinvention is also those compounds of the formula I which were alreadyknown per se and which are excluded by disclaimer from the above-definedcompounds of the formula I which are per se a subject of the presentinvention, and their physiologically acceptable salt as activators ofsoluble guanylate cyclase.

All statements above and below relating to the pharmacological effectsand the uses of the compounds of the formula I thus also apply to thecompound of the formula I wherein simultaneously the ring A² whichcomprises the carbon atoms which carry the groups C(═X)—NH— and NH—SO₂R²is a benzene ring which is substituted in positions 3 and 5 by chlorine,R² is methyl, X is oxygen and R¹—S(O)_(n)—A¹— is a5-chloro-2-(4-chlorophenylmercapto)-phenyl residue, and itsphysiologically acceptable salts.

Thus, a subject of the invention are, for example, said compound and itsphysiologically acceptable salts for use as a pharmaceutical,pharmaceutical preparations which comprise as active component aneffective dose of said compound and/or a physiologically acceptable saltthereof and a customary pharmaceutically acceptable carrier, and theuses of said compound and/or a physiologically acceptable salt thereofin the therapy or prophylaxis of the abovementioned syndromes as well astheir use for preparing medicaments for these purposes.

The pharmaceuticals according to the invention can be administeredorally, for example in the form of pills, tablets, lacquered tablets,sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous,alcoholic or oily solutions, syrups, emulsions or suspensions, orrectally, for example in the form of suppositories. Administration canalso be carried out parenterally, for example subcutaneously,intramuscularly or intravenously in the form of solutions for injectionor infusion. Other suitable administration forms are, for example,percutaneous or topical administration, for example in the form ofointments, tinctures, sprays or transdermal therapeutic systems, or theinhalative administration in the form of nasal sprays or aerosolmixtures, or, for example, microcapsules, implants or rods. Thepreferred administration form depends, for example, on the disease to betreated and on its severity.

The amount of active compound of the formula I and/or itsphysiologically acceptable salts in the pharmaceutical preparationsnormally is from 0.2 to 500 mg, preferably from 1 to 200 mg, per dose,but depending on the type of the pharmaceutical preparation it can alsobe higher. The pharmaceutical preparations usually comprise 0.5 to 90percent by weight of the compounds of the formula I and/or theirphysiologically acceptable salts. The preparation of the pharmaceuticalpreparations can be carried out in a manner known per se. For thispurpose, one or more compounds of the formula I and/or theirphysiologically acceptable salts, together with one or more solid orliquid pharmaceutical carrier substances and/or additives (or auxiliarysubstances) and, if desired, in combination with other pharmaceuticallyactive compounds having therapeutic or prophylactic action, are broughtinto a suitable administration form or dosage form which can then beused as a pharmaceutical in human or veterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Suitable carriers for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically sodium chloride solution, alcoholssuch as ethanol, glycerol, polyols, sucrose, invert sugar, glucose,mannitol, vegetable oils, etc. It is also possible to lyophilize thecompounds of the formula I and their physiologically acceptable saltsand to use the resulting lyophilisates, for example, for preparingpreparations for injection or infusion. Suitable carriers formicrocapsules, implants or rods are, for example, copolymers of glycolicacid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalpreparations can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the active compound of the formula I to be administeredand/or of a physiologically acceptable salt thereof depends on theindividual case and is, as is customary, to be adapted to the individualcircumstances to achieve an optimum effect. Thus, it depends on thenature and the severity of the disorder to be treated, and also on thesex, age, weight and individual responsiveness of the human or animal tobe treated, on the efficacy and duration of action of the compoundsused, on whether the therapy is acute or chronic or prophylactic, or onwhether other active compounds are administered in addition to compoundsof the formula I. In general, a daily dose of approximately 0.01 to 100mg/kg, preferably 0.1 to 10 mg/kg, in particular 0.3 to 5 mg/kg (in eachcase mg per kg of bodyweight) is appropriate for administration to anadult weighing approximately 75 kg in order to obtain the desiredresults. The daily dose can be administered in a single dose or, inparticular when larger amounts are administered, be divided intoseveral, for example two, three or four individual doses. In some cases,depending on the individual response, it may be necessary to deviateupwards or downwards from the given daily dose.

The compounds of the formula I activate the soluble guanylate cyclase,mainly by binding in the heme binding pocket of the enzyme. On accountof this property, apart from use as pharmaceutically active compounds inhuman medicine and veterinary medicine, they can also be employed as ascientific tool or as aids for biochemical investigations in which suchan effect on guanylate cyclase is intended, and also for diagnosticpurposes, for example in the in vitro diagnosis of cell samples ortissue samples. The compounds of the formula I and salts thereof canfurthermore be employed, as already mentioned above, as intermediatesfor the preparation of other pharmaceutically active compounds.

The following examples of compounds of the formula I and ofintermediates for their preparation illustrate the invention withoutlimiting it.

EXAMPLES 1.) 2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid

33.71 g (0.32 mol) of sodium carbonate were dissolved in 250 ml of waterand warmed to 60° C. 25.00 g (0.13 mol) of 2-amino-4,5-dimethoxy-benzoicacid were introduced into the solution, and to this solution 29.55 g(0.14 mol) of 4-chloro-benzenesulfonyl chloride were added portionwiseover 15 min . After cooling the mixture was filtered with suction, theresidue was taken up in 1% sodium hydrogencarbonate solution, thesolution filtered, and the product precipitated by addition of 1 Nhydrochloric acid. 25.90 g (55%) of2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid of meltingpoint (m.p.) 212-214° C. were obtained.

Analogously were obtained:

2.) 5-Chloro-2-(4-chloro-phenylsulfonylamino)-benzoic acid; M.p.: 210°C. 3.) 5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-benzoic acid 5.)2-(4-Chloro-phenylsulfonylamino)-cyclopentanecarboxylic acid; M.p.: 147°C. 6.) 2-(4-Chloro-phenylsulfonylamino)-5-methyl-benzoic acid; M.p.:201° C. 7.) 3-(4-Chloro-phenylsulfonylamino)-thiophene-2-carboxylicacid; M.p.: 180° C. 8.)3-(4-Chloro-phenylsulfonylamino)-pyrazole-4-carboxylic acid; Oil 9.)2-(4-Chloro-phenylsulfonylamino)-pyridine-3-carboxylic acid; M.p.:Decomposition (dec.)>360° C. 10.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride

25.90 g (0.07 mol) of2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid were mixedwith 75 ml of toluene, 17.30 g (0.08 mol) of phosphorus pentachloridewere added and the mixture was stirred at 40-45° C. for 2.5 h. Then themixture was concentrated in vacuo to half of its volume and the productthat precipitated was filtered off with suction and washed with a smallamount of toluene. 25.30 g (93%) of2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride having amelting point of 175-177° C. were obtained.

Analogously were obtained:

11.) 5-Chloro-2-(4-chloro-phenylsulfonylamino)-benzoyl chloride; M.p.:127° C. 12.) 5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-benzoylchloride; M.p.: 117° C. 13.)2-(4-Chloro-phenylsulfonylamino)-cyclopentanecarboxylic acid chloride;M.p.: 107° C. 14.) 2-(4-Chloro-phenylsulfonylamino)-5-methyl-benzoylchloride; M.p.: 114° C. 15.)3-(4-Chloro-phenylsulfonylamino)-thiophene-2-carboxylic acid chloride;M.p.: 122° C. 16.)3-(4-Chloro-phenylsulfonylamino)-pyrazole-4-carboxylic acid chloride;M.p.: 260° C. (Dec.) 17.)2-(4-Chloro-phenylsulfonylamino)-pyridine-3-carboxylic acid chloride18.)4-((2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-benzenesulfonylfluoride

10.00 g (25.6 mmol) of2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride weremixed with 300 ml of toluene, 4.49 g (25.6 mmol) of4-aminobenzenesulfonyl fluoride were added and the mixture was heatedunder reflux for 4 h. After cooling the precipitated solid was filteredoff with suction and washed with toluene. 11.71 g (87%) of the titlecompound having a melting point of 216-219° C. were obtained.

Analogously were obtained:

19.)4-((5-Chloro-2-(4-chloro-phenylsulfonylamino)-benzoyl)-amino)-benzenesulfonylfluoride; M.p.: 242° C. 20.)N-(4-Aminosulfonyl-phenyl)-5-chloro-2-(4-chloro-phenylsulfonylamino)-benzamide;M.p.: 260° C. 21.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-((4-(4-nitro-phenyl)-mercapto)-phenyl)-benzamide;M.p.: 255° C. 22.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(phenylmercapto)-phenyl)-benzamide;M.p.: 169° C. 23.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-methylmercapto-phenyl)-benzamide;M.p.: 220° C. 24.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-methyl-benzothiazol-5-yl)-benzamide;M.p.: 251° C. 25.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(3-diethylamino-2-hydroxy-propyl-mercapto)-phenyl)-benzamide;M.p.: 102° C. 26.)4-((5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-benzoyl)-amino)-benzenesulfonylfluoride; M.p.: 232° C. 27.)4-(2-(4-Chloro-phenylsulfonylamino)-cyclopentanecarbonylamino)-benzenesulfonylfluoride; M.p.: 211° C. 28.)4-((2-(4-Chloro-phenylsulfonylamino)-5-methyl-benzoyl)-amino)-benzenesulfonylfluoride; M.p.: 224° C. 29.)4-((3-(4-Chloro-phenylsulfonylamino)-thiophene-2-carbonyl)-amino)-benzenesulfonylfluoride; M.p.: 255° C. 30.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-mercapto-phenyl)-benzamide;M.p.: 202° C. 31.)4-((3-(4-Chloro-phenylsulfonylamino)-pyrazol-4-carbonyl)-amino)-benzenesulfonylfluoride; M.p.: 251° C. 32.)3-((5-Chloro-2-(4-chloro-phenylsulfonylamino)-benzoyl)-amino)-benzenesulfonylfluoride; M.p.: 224° C. 33.)4-(2-(4-Chloro-phenylsulfonylamino)-pyridine-3-carbonyl)-amino)-benzenesulfonylfluoride; M.p.: 263-265° C. 34.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-methyl-5-(thiomorpholine-4-sulfonyl)-thiazol-2-yl)-benzamide;M.p.: 265-267° C. 35.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-methylmercapto-phenyl)-benzamide36.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-methylmercapto-phenyl)-benzamide37.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(5-methyl-isoxazol-3-yl-sulfamoyl)-phenyl)-benzamide38.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-nitro-phenylsulfonyl)-phenyl)-benzamide39.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(5-ethylsulfonyl-2-hydroxy-phenyl)-benzamide40.)N-(3-Butylsulfamoyl-phenyl)-5-chloro-2-(4-chloro-phenylsulfonylamino)-benzamide41.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-nitro-5-propylmercapto-phenyl)-benzamide42.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-thiocyanato-phenyl)-benzamide43.)N-(4-Acetylsulfamoyl-phenyl)-5-chloro-2-(4-chloro-phenylsulfonylamino)-benzamide44.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-phenylmercapto-phenyl)-benzamide45.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-chloro-5-(2-cyano-ethylsulfamoyl)-phenyl)-benzamide46.)N-(5-Butylsulfamoyl-2-methoxy-phenyl)-5-chloro-2-(4-chloro-phenylsulfonylamino)-benzamide47.)N-(4-Benzoylsulfamoyl-phenyl)-5-chloro-2-(4-chloro-phenylsulfonylamino)-benzamide48.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-chloro-4-methylsulfonyl-phenyl)-benzamide49.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(hexadecylsulfonyl)-phenyl)-benzamide50.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(butylaminocarbonylaminosulfonyl)-phenyl)-benzamide51.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-sulfamoyl-phenyl)-benzamide52.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(2-methylmercapto-5-trifluoromethyl-phenyl)-benzamide53.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-methylsulfonyl-phenyl)-benzamide54.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-(2-hydroxy-ethylsulfonyl)-phenyl)-benzamide55.)(4-(5-Chloro-2-(4-chloro-phenylsulfonylamino)-benzoylamino)-phenylmercapto)-aceticacid 56.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(3,4-dimethyl-isoxazol-5-ylsulfamoyl)-phenyl)-benzamide57.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(thiazol-2-ylsulfamoyl)-phenyl)-benzamide58.)5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-N-(4-ethylmercapto-phenyl)-benzamide;M.p.: 171° C. 59.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide

500 mg (0.95 mmol) of4-((2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-benzenesulfonylfluoride were dissolved in 1 ml of thiomorpholine and heated to 90° C.for 30 min. For working up the mixture was poured onto 50 ml of ice/1 Nhydrochloric acid, the precipitate was filtered off with suction, driedin a vacuum-drying chamber over phosphorus pentoxide and recrystallizedfrom hexane/ethyl acetate. 378 mg (65%) of the title compound having amelting point of 241° C. were obtained.

Analogously were obtained:

60.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-pyridine-3-carboxamide;M.p.: 256-258° C. 61.)N-(4-(4-Carbamoyl-piperidine-1-sulfonyl)-phenyl)-2-(4-chloro-phenylsulfonylamino)-pyridine-3-carboxamide;M.p.: 273-276° C. 62.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(piperidine-1-sulfonyl)-phenyl)-pyridine-3-carboxamide;M.p.: 180-183° C. 63.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 246° C. 64.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-methyl-piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: 219° C. 65.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 259° C. 66.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 251° C. 67.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-hydroxy-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 255° C. 68.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(1,4-dioxa-8-aza-spiro[4.5]decane-8-sulfonyl)-phenyl)-benzamide;M.p.: 256° C. 69.)5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-N-(4-(morpholine4-sulfonyl)-phenyl)-benzamide;M.p.: 253° C. 70.)5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 222° C. 71.)5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-N-(4-(4-methyl-piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: 246° C. 72.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 172° C. 73.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: 277° C. 74.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-cyclopentanecarboxamide;M.p.: 180° C. 75.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-diethylsulfamoyl-phenyl)-benzamide;M.p.: 226° C. 76.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 240° C. 77.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(2-methoxy-ethylsulfamoyl)-phenyl)-benzamide;M.p.: 209° C. 78.)2-(4-Chloro-phenylsulfonylamino)-5-methyl-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 203° C. 79.)3-(4-Chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-thiophene-2-carboxamide;M.p.: 220° C. 80.)3-(4-Chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-1H-pyrazole-4-carboxamide;Oil 81.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 238° C. 82.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 202° C. 83.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(3-(4-methyl-piperazine-1-sulfonyl)-phenyl)-benzamidehydrochloride; M.p.: 245° C. 84.)3-(4-Chloro-phenylsulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-thiophene-2-carboxamide;M.p.: 229° C. 85.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 228° C. 86.)2-(4-Chloro-phenylsulfonylamino)-5-methyl-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 234° C. 87.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(4-methyl-piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: 172° C. 88.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 208° C. 89.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(4-hydroxy-piperidine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 244° C. 90.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(piperidine-3-sulfonyl)-phenyl)-benzamide;M.p.: 258° C. 91.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiazolidine-3-sulfonyl)-phenyl)-benzamide;M.p.: 261° C. 92.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(2,5-dihydro-1H-pyrrole-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 262° C. 93.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(1,2,3,6-tetrahydro-pyridine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 252° C. 94.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(2-methyl-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 227° C. 95.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: 243° C. 96.)4-(4-(2-(4-Chloro-phenylsulfonylamino)4,5-dimethoxy-benzoylamino)-phenylsulfonyl)-piperazine-1-carboxylicacid ethyl ester; M.p.: 245° C. 97.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(4-methyl-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 267° C. 98.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(4-methyl-perhydro-[1,4]diazepine-1-sulfonyl)-phenyl)-benzamide;M.p.: 274° C. 99.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(4-ethyl-piperazine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 191° C. 100.)2-(4-Chloro-phenylsulfonylamino)-N-(4-((2-dimethylamino-ethyl)-ethyl-sulfamoyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: Dec.>119° C. 101.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(1,4,5,6-tetrahydro-pyrimidine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: Dec.>237° C. 102.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(4-(pyrimidin-2-yl)-piperazine-1-sulfonyl)-phenyl)-benzamide;M.p.: Dec.>194° C. 103.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(4-(4-chloro-phenyl)-piperazine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: Dec.>243° C. 104.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(indan-1-ylsulfamoyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 161° C. 105.)2-(4-Chloro-phenylsulfonylamino)-N-(4-((2-(1H-info-3-yl)-ethyl)-methyl-sulfamoyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 182° C. 106.)1-(4-((2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-phenylsulfonyl)-piperidine-4-carboxamide;M.p.: 252° C. 107.)2-(4-Chloro-phenylsulfonylamino)-N-(4-cyclopropylsulfamoyl-phenyl)-4,5-dimethoxy-benzamide;M.p.: 222° C. 108.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(3-hydroxy-pyrrolidine-1-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;M.p.: 272° C. 109.)N-(4-(Allyl-cyclohexyl-sulfamoyl)-phenyl)-2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzamide;M.p.: 182° C. 110.)1-(4-((2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl)-amino)-phenylsulfonyl)-pyrrolidine-2-carboxylicacid; M.p.: 240° C. (sintering) 111.) 5-Chloro-2-nitro-benzoyl chloride

100.00 g (0.50 mol) of 5-chloro-2-nitrobenzoic acid were mixed with72.20 g (0.61 mol) of thionyl chloride and the mixture was heated underreflux for 2 h. The excess thionyl chloride was removed in vacuo. 106.50g (ca. 98%) of crude 5-chloro-2-nitro-benzoyl chloride were obtained asan oil.

Analogously was obtained:

112.) 5-Methyl-2-nitro-benzoyl chloride; Oil 113.)4-(5-Chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride

86.00 g (0.39 mol) of 5-chloro-2-nitro-benzoyl chloride was dissolved in300 ml of toluene, a solution of 62.00 g (0.35 mol) of4-aminobenzenesulfonyl fluoride was added dropwise, and the mixture washeated under reflux for 4 h. Subsequently it was cooled, concentrated invacuo to half of its volume, cooled, and the precipitated solid wasfiltered off with suction. 121.60 g (86%) of the title compound having amelting point of 182-184° C. were obtained.

Analogously were obtained:

114.) 4-(5-Methyl-2-nitro-benzoylamino)-benzenesulfonyl fluoride; M.p.:179° C. 115.) 5-Chloro-N-(4-ethylmercapto-phenyl)-2-nitro-benzamide116.) 5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-nitro-benzamide

120.00 g (0.33 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonylfluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) oftriethylamine were stirred in 1200 ml of toluene at 60° C. for 2 days.The precipitated solid was filtered off with suction and recrystallizedfrom acetone/n-hexane. 102.10 g (71%) of the title compound having amelting point of 243-245° C. were obtained.

Analogously were obtained:

117.)5-Chloro-2-nitro-N-(4-(thiomorpholone-4-sulfonyl)-phenyl)-benzamide;M.p.: 120° C. 118.)5-Methyl-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-nitro-benzamide; M p.:249° C. 119.)N-(4-(Morpholine-4-sulfonyl)-phenyl)-5-(morpholin-4-yl)-2-nitro-benzamide

20.00 g (0.56 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonylfluoride in 48.5 g (0.557 mol) of morpholine were heated under refluxfor 1 h. Subsequently the mixture was cooled, poured ontoice/hydrochloric acid and filtered with suction. 26.0 g (98%) of thetitle compound having a melting point of 252° C. were obtained.

120.) 2-Amino-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide

11.10 g (26. 1 mmol) of5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-nitro-benzamide weredissolved in 440 ml of tetrahydrofuran/methanol (1:1) and a solution of27.23 g (156.4 mmol) of sodium dithionite in 330 ml of water was addeddropwise. After stirring for 1 h at room temperature the organicsolvents were removed in rotary evaporator, and the precipitated productwas filtered off with suction and purified by chromatography over silicawith methylene chloride/methanol (9:1). 5.68 g (55%) of the titlecompound having a melting point of 229-231° C. were obtained.

Analogously were obtained:

121.)2-Amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 177° C. 122.)2-Amino-N-(4-(morpholine-4-sulfonyl)-phenyl)-(5-morpholin-4-yl)-benzamide;M.p.: 228° C. 123.)2-Amino-5-chloro-N-(4-ethylsulfonyl-phenyl)-benzamide; M.p.: 159-161° C.124.)5-Chloro-2-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl-amino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide

250 mg (0.60 mmol) of2-amino-5-chloro-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide weredissolved in 10 ml of dry pyridine, and a solution of 195 mg (0.85 mmol)5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride in 5 ml ofpyridine was added dropwise at 0° C. After 2 h the mixture was pouredonto ice, the precipitated solid was filtered off with suction andpurified by chromatography over silica with methylene chloride/methanol(98:2). 250 mg (69%) of the title compound having a melting point of215-216° C. were obtained.

Analogously were obtained:

125.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(4-methyl-phenylsulfonylamino)-benzamide;M.p.: 214° C. 126.)5-Chloro-2-(3,4-dimethoxy-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 245° C. 127.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(4-trifluoromethoxy-phenylsulfonylamino)-benzamide;M.p.: 195° C. 128.)2-((4-Acetylamino-phenyl)-sulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 198° C. 129.)5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 112° C. 130.)5-Chloro-2-(5-chloro-1,3-dimethyl-pyrazole-4-sulfonyl-amino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 161° C. 131.)5-Chloro-2-((1-methyl-imidazole-4-sulfonyl)-amino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 141° C. 132.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(pyridine-3-sulfonylamino)-benzamide;M.p.: 222° C. 133.)2-(4-Benzoyloxy-phenylsulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 245° C. 134.)5-Chloro-2-(ethylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 274-276° C. 135.)2-((2-Acetamideo-4-methyl-thiazole-5-sulfonyl)-amino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 257° C. 136.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(thiophene-2-sulfonylamino)-benzamide;M.p.: 216° C. 137.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(4-trifluoromethyl-phenylsulfonylamino)-benzamide;M.p.: 264° C. 138.)2-(4-Bromo-phenylsulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 232° C. 139.)2-(3,5-Bis-trifluoromethyl-phenylsulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 209° C. 140.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(4-nitro-phenylsulfonylamino)-benzamide;M.p.: 239° C. 141.)5-Chloro-2-(4-cyano-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 238° C. 142.)5-Chloro-2-(4-methylsulfonyl-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 181° C. 143.)5-Chloro-2-(4-isopropyl-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 105° C. 144.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-((2-phenyl-ethenyl)-sulfonylamino)-benzamide;M.p.: 278° C. 145.)5-Chloro-2-(4,5-dibromo-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 232° C. 146.)5-Chloro-2-(4-fluoro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 245° C. 147.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(5-phenylsulfonyl-thiophene-2-sulfonylamino)-benzamide;M.p.: 103° C. 148.)5-Chloro-2-(3-chloro-4-methoxy-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 274° C. 149.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(quinoline-8-sulfonylamino)-benzamide;M.p.: 262° C. 150.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(2,4,6-trimethyl-phenylsulfonylamino)-benzamide;M.p.: 240° C. 151.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(3-nitro-phenylsulfonylamino)-benzamide;M.p.: 220° C. 152.)5-Chloro-2-(4-methoxy-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 269° C. 153.)5-Chloro-2-methylsulfonylamino-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 248° C. 154.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-phenylmethylsulfonylamino-benzamide;M.p.: 106° C. 155.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(2,2,2-trifluoro-ethylsulfonylamino)-benzamide;M.p.: 208° C. 156.)2-(Butyl-sulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 102° C. 157.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(3-trifluoromethyl-phenylsulfonylamino)-benzamide;M.p.: 212° C. 158.0 )2-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 267° C. 159.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(2-trifluoromethyl-phenylsulfonylamino)-benzamide;M.p.: 234° C. 160.)5-Chloro-2-(3-chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 206° C. 161.)2-(4-Bromo-2-methoxy-phenylsulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 260° C. 162.)5-Chloro-2-(2,6-dichloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 244° C. 163.)5-Chloro-2-(2-cyano-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 200° C. 164.)2-(4-Butoxy-phenylsulfonylamino)-5-chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 225° C. 165.)5-Chloro-2-(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 120° C. 166.)5-Chloro-2-(3-fluoro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 204° C. 167.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-5-(morpholin-4-yl)-benzamide;M.p.: 264° C. 168.)5-Chloro-N-(4-ethylsulfonyl-phenyl)-2-(4-methyl-phenylsulfonylamino)-benzamide;M.p.: 188-192° C. 169.)5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: 195-197° C. 170.)5-Chloro-2-(4-chloro-3-nitro-phenylsulfonylamino)-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: 196-198° C. 171.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: 180-185° C. 172.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: Dec.>249° C. 173.)5-Chloro-2-ethylsulfonylamino-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: 103° C. 174.)4-Chloro-N-(2-(1H-benzimidazol-2-yl)-4-chloro-phenyl)-benzenesulfonamide

1.00 g (2.7 mmol) of 5-chloro-2-(4-chloro-phenylsulfonylamino)-benzoylchloride and 296 mg (2.7 mmol) of o-phenylenediamine in 150 ml oftoluene were heated under reflux for 1 h. A small amount of solid wasfiltered off with suction and the filtrate was evaporated. The residuewas taken up in 50 ml of toluene, 600 mg of thionyl chloride were addedand the mixture was again heated under reflux for 10 h. Subsequently itwas cooled and the precipitated solid was filtered off with suction. 280mg (25%) of the title compound having a melting point of 225-228° C.were obtained.

175.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(1,1-dioxo-thiomorpholine-4-sulfonyl)-phenyl)-benzamideand 176.)2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(1-oxo-thiomorpholine-4-sulfonyl)-phenyl)-benzamide

500 mg (0.82 mmol) of2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamidein 50 ml of acetone were cooled to 0° C. A solution of 371 mg (1.23mmol) of 57% m-chloroperbenzoic acid in 20 ml of acetone was added andthe mixture was stirred at room temperature over night. For working upit was poured onto water/ice and the precipitate was filtered off withsuction. The two products obtained as a mixture were separated bychromatography over silica with methylene chloride/methanol (97:3).

Analogously were obtained:

177.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(1,1-dioxo-thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 182° C. 178.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(1-oxo-thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 233° C. 179.)5-Chloro-2-(3,4-dichloro-phenylsulfonylamino)-N-(4-ethylsulfonyl-phenyl)-benzamide;M.p.: 240° C. 180.)5-Chloro-N-(4-ethylsulfonyl-phenyl)-2-nitro-benzamide 181.)4-Chloro-N-(4-chloro-2-(6-(morpholine-4-sulfonyl)-1H-benzimidazol-2-yl)-phenyl)-benzenesulfonamide

200 mg (0.5 mmol) of4-chloro-N-(2-(1H-benzimidazol-2-yl)-4-chloro-phenyl)-benzenesulfonamidewere added at 0° C. to 1 ml of chlorosulfuric acid and heated to 60 ° C.for 30 min. Subsequently the mixture was poured onto water/ice, and thesolid was filtered off with suction, dried and added at 0° C. to 1 ml ofmorpholine. After stirring at room temperature for 1 h the mixture waspoured onto ice/hydrochloric acid and extracted with ethyl acetate. Theextracts were evaporated and the residue was purified by chromatographyover silica with hexane/ethyl acetate (1:1). 20 mg (7%) of the titlecompound having a melting point of 225-228° C. were obtained.

¹H-NMR (D₆-DMSO): δ(ppm)=2.9 (m, 4 H, morpholine-H), 3.6 (m, 4 H,morpholine-H), 7.5 (dd, 4 H, phenylene-H), 7.4-8.2 (m, 6 H, benzo-H,phenyl-H)

182.)5-Chloro-N-(4-(morpholine-4-sulfonyl)-phenyl)-2-(2-(pyrrolidin-1-yl)-ethylsulfonylamino)-benzamide

The compound was prepared by using 2-chloro-ethylsulfonyl chloride. The1-(2-(4-chloro-2-(4-(morpholine-4-sulfonyl)-phenylcarbamoyl)-phenylsulfamoyl)-ethyl)-pyridiniumchloride that was isolated as an intermediate was reacted withpyrrolidine to give the title compound.

¹H-NMR (D₆-DMSO): δ(ppm)=1.8 (m, 4 H, pyrrolidine-H), 2.65 (m, 4 H,pyrrolidine-H), 3.0 (m, 4 H, morpholine-H), 3.1 (t, 2 H, ethylene-H),3.35 (t, 2 H, ethylene-H), 3.75 (m, 4 H, morpholine-H), 7.50 (dd, 1 H,H-4), 7.7 (d, 1 H, H-3), 7.75 (dd, 1 H, H-6), 7.85 (“dd”, 4 H,phenylene-H)

183.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-isopropylmercapto-phenyl)-benzamide

1.00 g (2.21 mmol) of5-chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-mercapto-phenyl)-benzamidewere dissolved in 25 ml of dimethylformamide and 0.25 g (2.21 mmol) ofpotassium tert-butylate were added. The mixture was stirred at roomtemperature for 15 min, then 0.27 g (2.21 mmol) of isopropyl bromidewere added dropwise, and the mixture was heated to 60° C. for 8 h. Forworking up it was poured onto water and extracted with ethyl acetate.The combined extracts were evaporated and the residue was purified bychromatography over silica with hexane/ethyl acetate (3:1). 420 mg (39%)of the title compound having a melting point of 168-169° C. wereobtained.

Analogously were obtained:

184.)5-Chloro-2-(4-chloro-phenylsufonylamino)-N-(4-cyanomethylmercapto-phenyl)-benzamide;M.p.: 104° C. 185.)(4-((5-Chloro-2-(4-chloro-phenysulfonylamino)-benzoyl)-amino)-phenylmercapto)-aceticacid ethyl ester; M.p.: 133° C. 186.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(2-(morpholin-4-yl)-ethylmercapto)-phenyl)-benzamide;M.p.: 95° C. 187.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(2-(2-methoxy-ethoxy)-ethylmercapto)-phenyl)-benzamide;Oil 188.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(prop-2-inyl)-mercapto-phenyl)-benzamide;M.p.: 185° C. 189.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-isopropylmercapto-phenyl)-benzamide;M.p.: 169° C. 190.)5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamidesodium salt

A mixture of 0.48 g finely powdered sodium hydroxide and 7 g of5-chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine4-sulfonyl)-phenyl)-benzamidein 250 ml of ethanol was brought into solution by short heating. Thenthe mixture was evaporated in vacuo, 50 ml of water were added and itwas again evaporated in vacuo to dryness. This procedure was repeatedtwice. The resulting product was dried in vacuo at 50° C. M.p.: 343° C.(Dec.)

Analogously to the above compounds the following example compounds wereobtained:

191.)4,5-Dimethoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(N-methyl-N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamidehydrochloride; M.p.: 214° C. 192.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(morpholine-4-sulfonyl)-3-methyl-phenyl)-benzamide;M.p.: 192° C. 193.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-3-methyl-phenyl)-benzamide;M.p.: 254° C. 194.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(3,5-dimethyl-piperidine-1-sulfonyl)-3-methyl-phenyl)-benzamide;M.p.: 242° C. 195.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(piperidine-1-sulfonyl)-3-methyl-phenyl)-benzamide;M.p.: 189° C. 196.)4,5-Dimethoxy-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(N-methyl-N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;M.p.: 213° C. 197.)4,5-Dimethoxy-2-(3,5-dimethyl-isoxazole-4sulfonylamino)-N-(4-(N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;M.p.: 216° C. 198.)5-Chloro-2-(2,4-dimethyl-thiazole-5-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 190° C. 199.)4,5-Dimethoxy-2-(4-chloro-phenylsulfonylamino)-N-(4-(3,5-dimethyl-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 249° C. (Dec.) 200.)2-(4-Chloro-phenylsulfonylamino)-N-(4-(N-methyl-N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;Resin 201.)3,4-Dimethoxy-2-(4-chloro-phenylsulfonylamino)-N-(4-(N-methyl-N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;M.p.: 241° C. 202.)5-Bromo-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-3-methyl-phenyl)-benzamide;M.p.: 249° C. 203.)5-Bromo-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 244° C. 204.)5-Bromo-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 197° C. 205.)4,5-Dimethoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(1,2,3,4-tetrahydro-isoquinoline-2-sulfonyl)-phenyl)-benzamide;M.p.: 213° C. 206.)4,5-Dimethoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 232° C. 207.)4,5-Dimethoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(cis-2,6-dimethyl-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 213° C. 208.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(1,2,3,4-tetrahydro-isoquinoline-2-sulfonyl)-phenyl)-benzamide;M.p.: 260° C. 209.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(N-methyl-N-(pyridin-3-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;M.p.: 65° C. (sintering) 210.)6-Methyl-2-(4-chloro-phenylsulfonylamino)-N-(4-(perhydroazepine-1-sulfonyl)-phenyl)-benzamide;M.p.: 151° C. 211.)6-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(pyrrolidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 217° C. 212.)6-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-hydroxybutylamino)-sulfonyl)-phenyl)-benzamide;Resin 213.)5-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(N-ethyl-N-(pyridin-4-yl-methyl)-aminosulfonyl)-phenyl)-benzamide;Resin 214.)2-(4-Chloro-phenylsulfonylamino)-N-(4-thiomorpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 209° C. 215.)3-Methyl-2-(4-chloro-phenylsulfonylamino)-N-(4-(N-methyl-N-(2-(pyridin-2-yl)-ethyl)-aminosulfonyl)-phenyl)-benzamide;M.p.: 193° C. 216.)4,5-Difluoro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-aminocarbonyl-piperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 227° C. 217.)4,5-Difluoro-2-(4-chloro-phenylsulfonylamino)-N-(4-(4-(2-hydroxyethyl)-piperazine-1-sulfonyl)-phenyl)-benzamide;Resin 218.)5-Chloro-4-methoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine4-sulfonyl)-phenyl)-benzamide;Oil 219.)5-Chloro-4-methoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-1-sulfonyl)-phenyl)-benzamide;M.p.: 89° C. 220.)5-Chloro-4-methoxy-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(N-pyridin-3-yl)-N-methyl-aminosulfonyl)-phenyl)-benzamide;M.p.: 135° C. 221.)4,5-Dimethoxy-2-(4-chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamidesodium salt; M.p.: 330° C. (Dec) 222.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide;M.p.: 230° C. 223.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(3,5-dimethylpiperidine-1-sulfonyl)-phenyl)-benzamide;M.p.: 61° C. 224.)5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(morpholine4-sulfonyl)-phenyl)-benzamide;M.p.: 286° C. 225.)5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-phenylsulfonyl)-phenyl)-benzamide;M.p.: 227° C. 226.)4-Chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine4-sulfonyl)-phenyl)-benzamide;M.p.: 103° C.

Pharmacological Investigations

(1) Activation of the Soluble Guanylate Cyclase

The activation of the soluble guanylate cyclase (sGC) which catalyzesthe conversion of guanosine triphosphate (GTP) into cyclic guanosinemonophosphate (cGMP) and pyrophosphate, by the compounds according tothe invention was quantified with the aid of an enzyme immunoassay (EIA)from Amersham. For this purpose the substances to be tested wereinitially incubated with sGC in microtiter plates, and the amount of thecGMP formed was then determined.

The sGC which was employed had been isolated from bovine lung (seeMethods in Enzymology, Volume 195, p. 377). The test solutions (100 μlper well) contained 50 mM triethanolamine (TEA) buffer (pH 7.5), 3 mMMgCl₂, 3 mM reduced glutathione (GSH), 0.1 mM GTP, 1 mM3-isobutyl-1-methylxanthine (IBMX), suitably diluted enzyme solution andthe substance to be tested or, in the control experiments, the solvent.The substances to be tested were dissolved in dimethyl sulfoxide (DMSO)and the solution was diluted with DMSO/water, so that the finalconcentration (c) of the substance to be tested in the test solution hadthe value indicated in the table. The DMSO concentration in the testsolution was 5% (v/v). The reaction was initiated by addition of thesGC. The reaction mixture was incubated at 37° C. for 15 to 20 minutesand then stopped by ice-cooling and addition of the stop reagent (50 mMEDTA, pH 8.0). An aliquot of 50 μl was taken and used for determiningthe cGMP content using the acetylation protocol of the Amersham cGMP-EIAkit. The absorption of the samples was measured at 450 nm (referencewavelength 620 nm) in a microtiter plate reader. The cGMP concentrationwas determined using a standard curve which was obtained under the sametest conditions. The activation of sGC by a test substance is given asthe n-fold stimulation of the basal enzyme activity which was found inthe control experiments (using solvent instead of test substance)(calculated using the formula n-foldstimulation=[cGMP]_(test substance)/[cGMP]_(control)).

The following results were obtained:

Compound of Concentration “c” Example No. [μM] “n-fold” stimulation 2350 14.7 59 50 34.8 63 50 33.9 64 50 23.9 65 50 24.6 66 50 33 67 50 29.668 50 12.1 69 50 28.3 70 50 25.1 71 50 13.4 72 50 27 73 50 16.5 75 505.1 76 50 10.6 77 50 5.9 79 50 15.4 84 50 23.7 86 50 32.9 87 50 12.5 8850 24.4 89 50 11.6 124 50 31.2 129 50 8.6 130 50 35.3 132 50 9.9 134 507.2 136 50 24.2 137 50 4.6 139 50 21.9 145 50 8 146 50 10.2 148 50 15.5150 50 15.3 151 50 19.9 155 50 7.8 156 50 7.8 157 50 4.6 175 50 21.1 17650 13.9 191 10 27.5 192 10 26.7 193 10 31.1 194  5 20.0 195 10 16.2 19610 21.9 206 50 19.3 208 10 23.1 209 10 28.5 222 10 29.5 223 10 27.1 22450 27.8 225 10 13.4 226 25 3.3

(2) Relaxation of Rat Aorta

For this test, normotensive male Wistar-Kyoto rats were sacrificed by ablow to the neck. The abdominal cavity and the thorax were opened by amedium sternotomy. The descending aorta was subsequently removed, freedof connective tissue and divided into 8 rings of a length ofapproximately 4 mm. The tip of a pair of tweezers was introduced intothe lumen of 4 of the 8 rings. The endothelium was removed by carefullyrolling the rings over the tip of the pair of tweezers. All 8 aortarings (4 with endothelium and 4 without endothelium) were subsequentlysuspended in an organ bath (Schuler-Organbad; Hugo Sachs Elektronik) ata constant temperature of 37° C. for the isometric determination of thecontractile tone. For 30 minutes, the rings were calibrated at a restingtension of 1 g in carbonated (95% O₂; 5% CO₂) Krebs-Henseleit solution(composition: Na⁺ 144.0 mM; K⁺ 5.9 mM; Cl⁻ 126.9 mM; Ca²⁺ 1.6 mM; Mg²⁺1.2 mM; H₂PO₄ ⁻ 1.2 mM; SO₄ ²⁻ 1.2 mM; HCO₃ ⁻ 25.0 mM; D-glucose 11.1mM) of pH 7.4. Additionally, 1 μmol/l of indomethacin were added to theKrebs-Henseleit solution to inhibit prostaglandin biosynthesis. Therings were subsequently precontracted by addition of phenylephrine(concentration in the solution: 1 μM) and the endothelium-dependentrelaxation or the functional loss of the endothelium was tested byaddition of acetylcholine (concentration in the solution: 1 μM). After a30-minute washing period, the rings were then again precontracted byaddition of phenylephrine (1 μM), and the relaxing action of the testsubstances of the formula I was determined by administration ofcumulative doses of the latter. The data were evaluated by standardmethods. Given is the concentration IC₅₀ by which contraction isinhibited by 50% (50% relaxation).

The following results were obtained:

Compound of Example No. IC₅₀ 59 ring without endothelium 0.27 μM 59 ringwith endothelium 0.52 μM 88 ring without endothelium 0.29 μM 88 ringwith endothelium 0.67 μM 129  ring without endothelium 0.31 μM 129  ringwith endothelium 0.46 μM

(3) Hemodynamic Effect in the Pig

Three pigs (German landrace) were anesthetized (Ketamine 20 mg/kg i.m.,Methomidate 8 mg/kg i.p., Xylazine 2.5 mg/kg i.m. and Pentobarbital 25mg/kg i.v. as a bolus plus 0.16 mg/kg per minute). The trachea wasintubated and the animals were given artificial respiration with air.Oxygen was added to keep the blood gas parameters in the normal range.To record the blood pressure (BP; BP(s)=systolic blood pressure,BP(d)=diastolic blood pressure) by means of a Statham 23 Db pressuretransducer a catheter was inserted into the right A. Femoralis. The leftventricular pressure (LVP), the left ventricular end-diastolic pressure(LVEDP), the contractility (dP/dt) and the heart rate (HR) weredetermined with a Millar PC 350 catheter “tip manometer” which wasinserted into the right ventricle. After a stabilization period of thehemodynamic parameters of 30 minutes the test substance was administeredin the indicated dose into the exposed duodenum by means of a catheter.The determined data were evaluated according to standard methods. Givenare the means and the standard deviations (M±SEM) of the starting valuesand of the maximal changes of the individual parameters (=maximaleffects).

The following results were obtained:

Compound of example 88 (dosage 10 mg/kg i.d.)

starting maximal duration of Parameter value alteration action (min)BP(s) (mm Hg) 123 ± 26  −23 ± 6 >180 BP(d) (mm Hg) 83 ± 24 −20 ± 8 >180LVEDP (mm Hg)   4 ± 0.6  −1.3 ± 0.3 >180 dP/dt_(max) (mm Hg/sec)) 1800 ±289  −633 ± 33 >180 HR (beats/min) 98 ± 2   −8 ± 2 >180

The invention may be embodied in other specific forms and those skilledin the art will recognize that various changes and modifications can bemade without departing from the spirit or essential characteristicsthereof. The present embodiment is, therefore, considered in allrespects as illustrative and not restrictive, the scope of the appendedclaims rather than by the foregoing description, and all changes whichcome within the meaning and range of equivalency of the claims aretherefore intended to be embraced therein.

We claim:
 1. A compound of formula I, a stereoisomeric form thereof, ora physiologically acceptable salt thereof:

wherein A¹ is a divalent residue chosen from phenylene and naphthylene,and is unsubstituted or substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₅)-alkyl, phenyl,tolyl, CF₃, NO₂, OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁—C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; A², which comprises the two carbon atoms bonded to thegroups C(═X)—NH— and NH—SO₂R², is a benzene ring, a naphthalene ring, ora saturated or partially unsaturated 3-membered to 7-memberedcarbocycle; R¹, when n in the group R¹—S(O)_(n)— is 0, is aryl,heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted or substituted byone or more identical or different residues R⁴, or is —CN, or when n inthe group R¹—S(O)_(n)— is 1, R¹ is aryl, heterocyclyl, or (C₁-C₁₈)-alkylwhich is unsubstituted or substituted by one or more identical ordifferent residues R⁴, or when n in the group R¹—S(O)_(n)— is 2, R¹ isaryl, heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴, or R¹ isNR⁵R⁶; R² is aryl, heterocyclyl, NR⁵R⁶, or (C₁-C₁₀)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴; R³ is one or more identical or different residues chosenfrom hydrogen, halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl, and (C₁-C₅)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R₄; R⁴ isfluorine, OH, —O—(C₁-C₁₀)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl,—O-aryl, —CN, NR⁷R⁸, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, oroxo; R⁵ is hydrogen, (C₁-C₁₀)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom R⁴ and aryl, or is aryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or—CO—(C₁-C₁₀)-alkyl wherein the alkyl residue is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁶ ishydrogen, (C₁-C₁₀)-alkyl which is unsubstituted or substituted by one ormore identical or different substituents chosen from R⁴ and aryl, or isaryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or —CO—(C₁-C₁₀)-alkyl whereinthe alkyl residue is unsubstituted or substituted by one or moreidentical or different residues R⁴; or R⁵ and R⁶ together with thenitrogen atom to which they are bonded form a 5-membered to 8-memberedsaturated or partially unsaturated ring, wherein said ring optionallyfurther comprises one or more ring heteroatoms chosen from nitrogen,oxygen, and sulfur, and wherein said ring is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom fluorine, (C₁-C₅)-alkyl, hydroxy-(C₁-C₃)-alkyl-,—(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, aryl, CF₃, OH, —O—(C₁-C₇)-alkyl,—O-aryl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, (C₂-C₃)-alkylenedioxy, NR⁷R⁸,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, CHO, —CO—(C₁-C₅)-alkyl, —S(O)_(n)(C₁-C₄)-alkyl,—S(O)_(n)—NH₂, —S(O)_(n)—NH—(C₁-C₃)-alkyl, —S(O)_(n)—N((C₁-C₃)-alkyl)₂,OXO, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—NH—(C₁-C₄)-alkyl, and—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ where in the substituent—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ the two alkyl groups are independent,identical or different, or are connected by a single bond and togetherwith the nitrogen atom to which they are bonded form a 5-membered to7-membered ring, which optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁷ is hydrogen or(C₁-C₇)-alkyl which is unsubstituted or substituted by one or moreidentical or different substituents chosen from OH, —O—(C₁-C₅)-alkyl,NH₂, —NH—(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂ where in the substituentN((C₁-C₄)-alkyl)₂ the two alkyl groups are independent, identical ordifferent, or are connected by a single bond and together with thenitrogen atom to which they are bonded form a 5-membered to 7-memberedring, wherein said ring optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁸ is hydrogen,—CO—(C₁-C₄)-alkyl, or (C₁-C₇)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom OH, —O—(C₁-C₅)-alkyl, NH₂, —NH—(C₁-C₄)-alkyl, and—N((C₁-C₄)-alkyl)₂ where in the substituent N((C₁-C₄)-alkyl)₂ the twoalkyl groups are independent, identical or different, or are connectedby a single bond and together with the nitrogen atom to which they arebonded form a 5-membered to 7-membered ring which optionally furthercomprises an oxygen atom, a sulfur atom, or a group NR⁵ as ring member;aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, —O—CF₃, NO₂, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, -S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; heteroaryl is a residue of a monocyclic 5-membered or6-membered aromatic heterocycle or of a bicyclic 8-membered to10-membered aromatic heterocycle, wherein said heterocycles comprise oneor more ring heteroatoms chosen from nitrogen, oxygen, and sulfur;heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to11-membered saturated or partially unsaturated heterocycle whichcomprises one or more ring heteroatoms chosen from nitrogen, oxygen, andsulfur, and which is unsubstituted or substituted by one or moreidentical or different substituents chosen from fluorine, (C₁-C₅)-alkyl,OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —CN, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH, and—CO—O—(C₁-C₅)-alkyl; n is 0, 1, or 2; m is 2, 3, or 4; and X is oxygenor NH, or X is a nitrogen atom which via a single bond is attached to aring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ bonded to the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ bonded to itforms an anellated imidazole ring; excluding the compound of formula Iwherein simultaneously A² is a benzene ring which is substituted inpositions 3 and 5 by chlorine, R² is methyl, X is oxygen, andR¹—S(O)_(n)-A¹- is a 5-chloro-2-(4-chlorophenylmercapto)-phenyl residue.2. The compound of the formula I as claimed in claim 1, wherein A¹ is aphenylene residue that is unsubstituted or substituted as set forth inclaim
 1. 3. The compound of the formula I as claimed in claim 1, whereinA² is an aromatic ring.
 4. The compound of the formula I as claimed inclaim 1, wherein X is oxygen.
 5. The compound of the formula I asclaimed in claim 1, wherein R² is aryl and is unsubstituted orsubstituted as set forth in claim
 1. 6. The compound of the formula I asclaimed in claim 1, wherein R¹ is (C₁-C₇)-alkyl, aryl, or NR⁵R⁶, and isunsubstituted or substituted as set forth in claim
 1. 7. The compound ofthe formula I as claimed in claim 1, wherein R¹ is NR⁵R⁶ and R⁵ and R⁶independently of one another are hydrogen, (C₁—C₉)-alkyl,(C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl-, or 5-membered or 6-membered aryl or R⁵and R⁶ together with the nitrogen atom to which they are bonded form a5-membered to 7-membered heterocycle which optionally further comprisesan additional ring heteroatom chosen from nitrogen, oxygen, and sulfur,wherein said heterocycle is unsubstituted or substituted by one or moreidentical or different residues chosen from (C₁-C₃)-alkyl,hydroxy-(C₁-C₃)-alkyl-, 5-membered or 6-membered aryl, carbamoyl,hydroxy, and oxo.
 8. The compound of the formula I as claimed in claim1, wherein A¹ is phenylene and is unsubstituted or substituted by one ormore identical or different substituents chosen from halogen,(C₁-C₄)-alkyl, CF₃, —O—(C₁-C₄)-alkyl, and —CN; A² is an aromatic ring;R¹, when n in the group R¹—S(O)_(n)— is 1, is (C₁-C₇)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴, or R¹ is aryl, or when n in the group R¹—S(O)_(n)— is 2, R¹is aryl, or (C₁-C₇)-alkyl which is unsubstituted or substituted by oneor more identical or different residues R⁴, or R¹ is NR⁵R⁶; R² is aryl;R³ is one or more identical or different residues chosen from hydrogen,halogen, CF₃, OH, —O—(C₁-C₄)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₄)-alkyl,—O-aryl, NO₂, —CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₄)-alkyl,heterocyclyl, —S(O)_(n)—(C₁-C₄)-alkyl, and (C₁-C₄)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴; R⁴ is fluorine, OH, —O—(C₁-C₁₀)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, —CN, NR⁷R⁸, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₄)-alkyl, heterocyclyl, or oxo; R⁵ and R⁶ independently ofone another are hydrogen, (C₁-C₉)-alkyl, (C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl-,or aryl, or R⁵ and R⁶ together with the nitrogen to which they arebonded form a 5-membered, 6-membered, or 7-membered heterocycle, whereinsaid heterocycle optionally further comprises an additional ringheteroatom chosen from nitrogen, oxygen, and sulfur, and wherein saidheterocycle is unsubstituted or substituted by one or more identical ordifferent residues chosen from (C₁-C₃)-alkyl, hydroxy-(C₁-C₃)-alkyl-,aryl, carbamoyl, hydroxy, and oxo; R⁷ is hydrogen, (C₁-C₃)-alkyl,((C₁-C₄)-alkyl)₂N—(C₁-C₃)-alkyl-, or (C₁-C₄)-alkyl-O—(C₁-C₃)-alkyl-; R⁸is hydrogen, (C₁-C₃)-alkyl, or acetyl; aryl is phenyl or heteroaryl, andis unsubstituted or substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, phenyl, CF₃, NO₂,—O—(C₁-C₄)-alkyl, (C₁-C₂)-alkylenedioxy, NH₂, —NH—CO—(C₁-C₄)-alkyl, —CN,—CO—NH₂, —CO—OH, and —CO—O—(C₁-C₄)-alkyl; heteroaryl is a residue of amonocyclic 5-membered or 6-membered aromatic heterocycle which comprisesone or more identical or different ring heteroatoms chosen fromnitrogen, oxygen, and sulfur; heterocyclyl is a residue of a monocyclic5-membered or 6-membered saturated heterocycle which comprises one ormore identical or different ring heteroatoms chosen from nitrogen,oxygen, and sulfur, and which is unsubstituted or substituted by one ormore identical or different substituents chosen from fluorine,(C₁-C₄)-alkyl, OH, —O—(C₁-C₄)-alkyl, NH₂, —CN, —CO—NH₂, —CO—OH, and—CO—O—(C₁-C₄)-alkyl; n is 0, 1, or 2; and X is oxygen.
 9. The compoundof the formula I as claimed in claim 1, wherein A¹ is phenylene which isunsubstituted or substituted by one or more identical or differentsubstituents chosen from halogen, (C₁-C₄)-alkyl, CF₃, —O—(C₁-C₄)-alkyl,and —CN; A² is a benzene ring; R¹ is NR⁵R⁶; R²aryl; R³ is one or moreidentical or different residues chosen from hydrogen, halogen, CF₃,—O—(C₁-C₄)-alkyl, —CN, and (C₁-C₄)-alkyl; R⁵ and R⁶ together with thenitrogen atom to which they are bonded form a 5-membered or 6-memberedsaturated heterocycle, wherein said heterocycle optionally furthercomprises an additional ring heteroatom chosen from nitrogen, oxygen,and sulfur, and said heterocycle is unsubstituted or substituted by oneor more identical or different residues chosen from (C₁-C₃)-alkyl,hydroxy-(C₁-₃)-alkyl-, aryl, carbamoyl, hydroxy, and oxo; aryl is phenylor 5-membered or 6-membered heteroaryl comprising one or more identicalor different ring heteroatoms chosen from nitrogen, oxygen, and sulfur,and is unsubstituted or substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₄)-alkyl, CF₃, NO₂,—O—(C₁-C₄)-alkyl, —NH—CO—(C₁-₄)-alkyl, and —CN; n is 2; and X is oxygen.10. The compound of the formula I as claimed in claim 1, wherein A¹ isan unsubstituted divalent phenylene residue; A² is a benzene ring; R¹ isNR⁵R⁶; R² is aryl; R³ is one or more identical or different residueschosen from hydrogen, halogen, —O—(C₁-₄)-alkyl, and (C₁-C₄)-alkyl; R⁵and R⁶ together with the nitrogen atom to which they are bonded form asaturated 6-membered heterocycle which optionally further comprises anadditional ring heteroatom chosen from nitrogen, oxygen, and sulfur,said heterocycle is unsubstituted or substituted by one or moreidentical or different residues chosen from (C₁-C₃)-alkyl, aryl, oxo andcarbamoyl; aryl is phenyl or 5-membered or 6-membered heteroarylcomprising one or more identical or different ring heteroatoms chosenfrom nitrogen, oxygen, and sulfur, and is unsubstituted or substitutedby one or more identical or different substituents chosen from halogen,(C₁-C₄)-alkyl, CF₃, and —O—(C₁-C₄)-alkyl; n is 2; and X is oxygen. 11.The compound of the formula I as claimed in claim 1, wherein A¹ is anunsubstituted divalent 1,4-phenylene residue; A², together with theresidues R³, is a benzene ring which is substituted with one or twoidentical or different substituents chosen from chlorine and methoxy; R¹is NR⁵R⁶; R² is phenyl or thienyl, and is substituted by one or twochlorine atoms; R⁵ and R⁶ together with the nitrogen atom to which theyare bonded form a saturated 6-membered heterocycle which optionallyfurther comprises an additional ring heteroatom chosen from oxygen andsulfur, and which is unsubstituted or substituted by one or two methylresidues; n is 2; and X is oxygen.
 12. The compound of the formula I asclaimed in claim 1, wherein said compound is chosen from:2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide;2-(4-Chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide;5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide;5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide;and pharmaceutically acceptable salts of any of the foregoing.
 13. Thecompound of the formula I as claimed in claim 12, wherein saidpharmaceutically acceptable salts are sodium salts.
 14. A compound2-(4-Chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide,or a pharmaceutically acceptable salt thereof.
 15. The compound asclaimed in claim 14, wherein said pharmaceutically acceptable salt isthe sodium salt.
 16. A compound2-(4-Chloro-phenylsulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-4,5-dimethoxy-benzamide,a stereoisomeric form thereof, or a pharmaceutically acceptable salt ofany of the foregoing.
 17. The compound as claimed in claim 16, whereinsaid pharmaceutically acceptable salt is the sodium salt.
 18. A compound5-Chloro-2-(5-chloro-thiophene-2-sulfonylamino)-N-(4-(morpholine-4-sulfonyl)-phenyl)-benzamide,or a pharmaceutically acceptable salt thereof.
 19. The compound asclaimed in claim 18, wherein said pharmaceutically acceptable salt isthe sodium salt.
 20. A compound5-Chloro-2-(3,5-dimethyl-isoxazole-4-sulfonylamino)-N-(4-(cis-2,6-dimethyl-morpholine-4-sulfonyl)-phenyl)-benzamide,a stereoisomeric form thereof, or a pharmaceutically acceptable salt ofany of the foregoing.
 21. The compound as claimed in claim 20, whereinsaid pharmaceutically acceptable salt is the sodium salt.
 22. A methodfor preparing a compound of formula I, comprising: converting a cyclicaminocarboxylic acid compound of formula II into asulfonylaminocarboxylic acid compound of formula III; and converting thesulfonylaminocarboxylic acid compound of formula III into a compound offormula I:

 wherein, in the compounds of formulae I, II, and III: A¹ is a divalentresidue chosen from phenylene and naphthylene, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, NO₂, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁—C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; A², which comprises the two carbon atoms bonded to thegroups C(═X)—NH— and NH—SO₂R², is a benzene ring, a naphthalene ring, ora saturated or partially unsaturated 3-membered to 7-memberedcarbocycle; R¹, when n in the group R¹—S(O)_(n)— is 0, is aryl,heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted or substituted byone or more identical or different residues R⁴, or is —CN, or when n inthe group R¹—S(O)_(n)— is 1, R¹ is aryl, heterocyclyl, or (C₁-C₁₈)-alkylwhich is unsubstituted or substituted by one or more identical ordifferent residues R⁴, or when n in the group R¹—S(O)_(n)— is 2, R¹ isaryl, heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴, or R¹ isNR⁵R⁶; R² is aryl, heterocyclyl, NR⁵R⁶, or (C₁-C₁₀)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴; R³ is one or more identical or different residues chosenfrom hydrogen, halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl, and (C₁-C₅)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R₄; R⁴ isfluorine, OH, —O—(C₁-C₁₀)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl,—O-aryl, —CN, NR⁷R⁸, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, oroxo; R⁵ is hydrogen, (C₁-C₁₀)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom R⁴ and aryl, or is aryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or—CO—(C₁-C₁₀)-alkyl wherein the alkyl residue is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁶ ishydrogen, (C₁-C₁₀)-alkyl which is unsubstituted or substituted by one ormore identical or different substituents chosen from R⁴ and aryl, or isaryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or —CO—(C₁-C₁₀)-alkyl whereinthe alkyl residue is unsubstituted or substituted by one or moreidentical or different residues R⁴; or R⁵ and R⁶ together with thenitrogen atom to which they are bonded form a 5-membered to 8-memberedsaturated or partially unsaturated ring, wherein said ring optionallyfurther comprises one or more ring heteroatoms chosen from nitrogen,oxygen, and sulfur, and wherein said ring is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom fluorine, (C₁-C₅)-alkyl, hydroxy-(C₁-C₃)-alkyl-,—(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, aryl, CF₃, OH, —O—(C₁-C₇)-alkyl,—O-aryl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, (C₂-C₃)-alkylenedioxy, NR⁷R⁸,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, CHO, —CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl,—S(O)_(n)—NH₂, —S(O)_(n)—NH—(C₁-₃)-alkyl, —S(O)_(n)—N((C₁-C₃)-alkyl)₂,oxo, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—NH—(C₁-C₄)-alkyl, and—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ where in the substituent—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ the two alkyl groups are independent,identical or different, or are connected by a single bond and togetherwith the nitrogen atom to which they are bonded form a 5-membered to7-membered ring, which optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁷ is hydrogen or(C₁-C₇)-alkyl which is unsubstituted or substituted by one or moreidentical or different substituents chosen from OH, —O—(C₁-C₅)-alkyl,NH₂, —NH—(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂ where in the substituentN((C₁-C₄)-alkyl)₂ the two alkyl groups are independent, identical ordifferent, or are connected by a single bond and together with thenitrogen atom to which they are bonded form a 5-membered to 7-memberedring, wherein said ring optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁸ is hydrogen,—CO—(C₁-C₄)-alkyl, or (C₁-C₇)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom OH, —O—(C₁-C₅)-alkyl, NH₂, —NH—(C₁-C₄)-alkyl, and—N((C₁-C₄)-alkyl)₂ where in the substituent N((C₁-C₄)-alkyl)₂ the twoalkyl groups are independent, identical or different, or are connectedby a single bond and together with the nitrogen atom to which they arebonded form a 5-membered to 7-membered ring which optionally furthercomprises an oxygen atom, a sulfur atom, or a group NR⁵ as ring member;aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, —O—CF₃, NO₂, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; heteroaryl is a residue of a monocyclic 5-membered or6-membered aromatic heterocycle or of a bicyclic 8-membered to10-membered aromatic heterocycle, wherein said heterocycles comprise oneor more ring heteroatoms chosen from nitrogen, oxygen, and sulfur;heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to11-membered saturated or partially unsaturated heterocycle whichcomprises one or more ring heteroatoms chosen from nitrogen, oxygen, andsulfur, and which is unsubstituted or substituted by one or moreidentical or different substituents chosen from fluorine, (C₁-C₅)-alkyl,OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —CN, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH, and—CO—O—(C₁-C₅)-alkyl; n is
 0. 1, or 2; m is 2, 3, or 4; and X is oxygenor NH, or X is a nitrogen atom which via a single bond is attached to aring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ bonded to the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ bonded to itforms an anellated imidazole ring; or when one or more of said residues,independent of each other, are present in protected form or in a form ofprecursor groups.
 23. A method for preparing a compound of formula I,comprising: converting a cyclic nitrocarboxylic acid compound of formulaIX into a nitrocarboxamide compound of formula XII; and converting thenitrocarboxamide compound of the formula XII into a compound of formulaI by reducing the nitro group to an amino group, and sulfonylating theamino group:

 wherein, in the compounds of formulae IX, XII, and I: A¹ is a divalentresidue chosen from phenylene and naphthylene, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, NO₂, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; A², which comprises the two carbon atoms bonded to thegroups C(═X)—NH— and NH—SO₂R², is a benzene rings a naphthalene ring, ora saturated or partially unsaturated 3-membered to 7-memberedcarbocycle; R¹, when n in the group R¹—S(O)_(n)— is 0, is aryl,heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted or substituted byone or more identical or different residues R⁴, or is —CN, or when n inthe group R¹—S(O)_(n)— is 1, R¹ is aryl, heterocyclyl, or (C₁-C₁₈)-alkylwhich is unsubstituted or substituted by one or more identical ordifferent residues R⁴, or when n in the group R¹—S(O)_(n)— is 2, R¹ isaryl, heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴, or R¹ isNR⁵R⁶; R² is aryl, heterocyclyl, NR⁵R⁶, or (C₁-C₁₀)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴; R³ is one or more identical or different residues chosenfrom hydrogen, halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl, and (C₁-C₅)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁴ isfluorine, OH, —O—(C₁-C₁₀)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl,—O-aryl, —CN, NR⁷R⁸, —CO—NH₂, —CO—NH—(C₁—C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, oroxo; R⁵ is hydrogen, (C₁-C₁₀)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom R⁴ and aryl, or is aryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or—CO—(C₁-C₁₀)-alkyl wherein the alkyl residue is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁶ ishydrogen, (C₁-C₁₀)-alkyl which is unsubstituted or substituted by one ormore identical or different substituents chosen from R⁴ and aryl, or isaryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or —CO—(C₁-C₁₀)-alkyl whereinthe alkyl residue is unsubstituted or substituted by one or moreidentical or different residues R⁴; or R⁵ and R⁶ together with thenitrogen atom to which they are bonded form a 5-membered to 8-memberedsaturated or partially unsaturated ring, wherein said ring optionallyfurther comprises one or more ring heteroatoms chosen from nitrogen,oxygen, and sulfur, and wherein said ring is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom fluorine, (C₁-C₅)-alkyl, hydroxy-(C₁-C₃)-alkyl-,—(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, aryl, CF₃, OH, —O—(C₁-C₇)-alkyl,—O-aryl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, (C₂-C₃)-alkylenedioxy, NR⁷R⁸,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, CHO, —CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl,—S(O)_(n)—NH₂, —S(O)_(n)—NH—(C₁-C₃)-alkyl, —S(O)_(n)—N((C₁-C₃)-alkyl)₂,oxo, —(CH₂)_(m)—NH₂, —(CH₂)_(m)—NH—(C₁-C₄)-alkyl, and—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ where in the substituent—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ the two alkyl groups are independent,identical or different, or are connected by a single bond and togetherwith the nitrogen atom to which they are bonded form a 5-membered to7-membered ring, which optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁷ is hydrogen or(C₁-C₇)-alkyl which is unsubstituted or substituted by one or moreidentical or different substituents chosen from OH, —O—(C₁-C₅)-alkyl,NH₂, —NH—(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂ where in the substituentN((C₁-C₄)-alkyl)₂ the two alkyl groups are independent, identical ordifferent, or are connected by a single bond and together with thenitrogen atom to which they are bonded form a 5-membered to 7-memberedring, wherein said ring optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁸ is hydrogen,—CO—(C₁-C₄)-alkyl, or (C₁-C₇)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom OH, —O—(C₁-C₅)-alkyl, NH₂, —NH—(C₁C-C₄)-alkyl, and—N((C₁-₄)-alkyl)₂ where in the substituent N((C₁-C₄)-alkyl)₂ the twoalkyl groups are independent, identical or different, or are connectedby a single bond and together with the nitrogen atom to which they arebonded form a 5-membered to 7-membered ring which optionally furthercomprises an oxygen atom, a sulfur atom, or a group NR⁵ as ring member;aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, —O—CF₃, NO₂, OH,—O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁C-₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; heteroaryl is a residue of a monocyclic 5-membered or6-membered aromatic heterocycle or of a bicyclic 8-membered to10-membered aromatic heterocycle, wherein said heterocycles comprise oneor more ring heteroatoms chosen from nitrogen, oxygen, and sulfur;heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to11-membered saturated or partially unsaturated heterocycle whichcomprises one or more ring heteroatoms chosen from nitrogen, oxygen, andsulfur, and which is unsubstituted or substituted by one or moreidentical or different substituents chosen from fluorine, (C₁-C₅)-alkyl,OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —CN, —CO—NH₂,—CO—NH—(C₁—C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH, and—CO—O—(C₁-C₅)-alkyl; n is 0, 1, or 2; m is 2, 3, or 4; and X is oxygenor NH, or X is a nitrogen atom which via a single bond is attached to aring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ bonded to the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ bonded to itforms an anellated imidazole ring; or when one or more of said residues,independent of each other, are present in protected form or in a form ofprecursor groups.
 24. A composition, comprising a compound of formula I:

wherein A¹ is a divalent residue chosen from phenylene and naphthylene,and is unsubstituted or substituted by one or more identical ordifferent substituents chosen from halogen, (C₁-C₅)-alkyl, phenyl,tolyl, CF₃, NO₂, OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl,(C₁-C₂)-alkylenedioxy, NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂,—NH—CHO, —NH—CO—(C₁-C₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; A², which comprises the two carbon atoms bonded to thegroups C(═X)—NH— and NH—SO₂R², is a benzene ring, a naphthalene ring, ora saturated or partially unsaturated 3-membered to 7-memberedcarbocycle; R¹, when n in the group R¹—S(O)_(n)— is 0, is aryl,heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted or substituted byone or more identical or different residues R⁴, or is —CN, or when n inthe group R¹—S(O)_(n)— is 1, R¹ is aryl, heterocyclyl, or (C₁-C₁₈)-alkylwhich is unsubstituted or substituted by one or more identical ordifferent residues R⁴, or when n in the group R¹—S(O)_(n)— is 2, R¹ isaryl, heterocyclyl, or (C₁-C₁₈)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴, or R¹ isNR⁵R⁶; R² is aryl, heterocyclyl, NR⁵R⁶, or (C₁-C₁₀)-alkyl which isunsubstituted or substituted by one or more identical or differentresidues R⁴; R³ is one or more identical or different residues chosenfrom hydrogen, halogen, CF₃, OH, —O—(C₁-C₇)-alkyl,—O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, —O-aryl, (C₁-C₂)-alkylenedioxy, NO₂,—CN, NR⁷R⁸, —CO—NR⁷R⁸, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl,—S(O)_(n)—(C₁-C₅)-alkyl, and (C₁-C₅)-alkyl which is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁴ isfluorine, OH, —O—(C₁-C₁₀)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl,—O-aryl, —CN, NR⁷R⁸, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, oroxo; R⁵ is hydrogen, (C₁-₁₀)-alkyl which is unsubstituted or substitutedby one or more identical or different substituents chosen from R⁴ andaryl, or is aryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or—CO—(C₁-C₁₀)-alkyl wherein the alkyl residue is unsubstituted orsubstituted by one or more identical or different residues R⁴; R⁶ ishydrogen, (C₁-C₁₀)-alkyl which is unsubstituted or substituted by one ormore identical or different substituents chosen from R⁴ and aryl, or isaryl, heterocyclyl, —CO—NR⁷R⁸, —CO-aryl, or —CO—(C₁-C₁₀)-alkyl whereinthe alkyl residue is unsubstituted or substituted by one or moreidentical or different residues R⁴; or R⁵ and R⁶ together with thenitrogen atom to which they are bonded form a 5-membered to 8-memberedsaturated or partially unsaturated ring, wherein said ring optionallyfurther comprises one or more ring heteroatoms chosen from nitrogen,oxygen, and sulfur, and wherein said ring is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom fluorine, (C₁-C₅)-alkyl, hydroxy-(C₁-C₃)-alkyl-,—(C₁-C₃)-alkyl-O—(C₁-C₄)-alkyl, aryl, CF₃, OH, —O—(C₁-C₇)-alkyl,—O-aryl, —O—(C₂-C₄)-alkyl-O—(C₁-C₇)-alkyl, (C₂-C₃)-alkylenedioxy, NR⁷R⁸,—CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH,—CO—O—(C₁-C₅)-alkyl, CHO, —CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl,—S(O)_(n)—NH₂, —S(O)_(n)—NH—(C₁-C₃)-alkyl, —S(O)_(n)—N((C₁-C₃)-alkyl)₂,oxo, —(CH₂)_(m)—NH₂, -(CH₂)_(m)—NH—(C₁-₄)-alkyl, and—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ where in the substituent—(CH₂)_(m)—N((C₁-C₄)-alkyl)₂ the two alkyl groups are independent,identical or different, or are connected by a single bond and togetherwith the nitrogen atom to which they are bonded form a 5-membered to7-membered ring, which optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁷ is hydrogen or(C₁-C₇)-alkyl which is unsubstituted or substituted by one or moreidentical or different substituents chosen from OH, —O—(C₁-C₅)-alkyl,NH₂, —NH—(C₁-C₄)-alkyl, and —N((C₁-C₄)-alkyl)₂ where in the substituentN((C₁-C₄)-alkyl)₂ the two alkyl groups are independent, identical ordifferent, or are connected by a single bond and together with thenitrogen atom to which they are bonded form a 5-membered to 7-memberedring, wherein said ring optionally further comprises an oxygen atom,sulfur atom, or a group NR⁵ as a ring member; R⁸ is hydrogen,—CO—(C₁-C₄)-alkyl, or (C₁-C₇)-alkyl which is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom OH, —O—(C₁-C₅)-alkyl, NH₂, —NH—(C₁-C₄)-alkyl, and—N((C₁-C₄)-alkyl)₂ where in the substituent N((C₁-C₄)-alkyl)₂ the twoalkyl groups are independent, identical or different, or are connectedby a single bond and together with the nitrogen atom to which they arebonded form a 5-membered to 7-membered ring which optionally furthercomprises an oxygen atom, a sulfur atom, or a group NR⁵ as ring member;aryl is phenyl, naphthyl, or heteroaryl, and is unsubstituted orsubstituted by one or more identical or different substituents chosenfrom halogen, (C₁-C₅)-alkyl, phenyl, tolyl, CF₃, —O—CF₃, NO₂, OH,—O—(C₁-₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, (C₁-₂)-alkylenedioxy,NH₂, —NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —NH—CHO,—NH—CO—(C₁-₅)-alkyl, —CN, —CO—NH₂, —CO—NH—(C₁-C₃)-alkyl,—CO—N((C₁-C₃)-alkyl)₂, —CO—OH, —CO—O—(C₁-C₅)-alkyl, heterocyclyl, CHO,—CO—(C₁-C₅)-alkyl, —S(O)_(n)—(C₁-C₄)-alkyl, —S(O)_(n)-phenyl, and—S(O)_(n)-tolyl; heteroaryl is a residue of a monocyclic 5-membered or6-membered aromatic heterocycle or of a bicyclic 8-membered to10-membered aromatic heterocycle, wherein said heterocycles comprise oneor more ring heteroatoms chosen from nitrogen, oxygen, and sulfur;heterocyclyl is a residue of a monocyclic or polycyclic 5-membered to11-membered saturated or partially unsaturated heterocycle whichcomprises one or more ring heteroatoms chosen from nitrogen, oxygen, andsulfur, and which is unsubstituted or substituted by one or moreidentical or different substituents chosen from fluorine, (C₁-C₅)-alkyl,OH, —O—(C₁-C₅)-alkyl, —O—(C₂-C₄)-alkyl-O—(C₁-C₃)-alkyl, NH₂,—NH—(C₁-C₃)-alkyl, —N((C₁-C₃)-alkyl)₂, —CN, —CO—NH₂,—CO—NH—(C₁-C₃)-alkyl, —CO—N((C₁-C₃)-alkyl)₂, —CO—OH, and—CO—O—(C₁-C₅)-alkyl; n is 0, 1, or 2; m is 2, 3, or 4; and X is oxygenor NH, or X is a nitrogen atom which via a single bond is attached to aring carbon atom in the group A¹ which ring carbon atom is directlyadjacent to the carbon atom in A¹ bonded to the group —NH—C(═X)— so thatthe group —NH—C(═X)— together with the carbon atoms in A¹ bonded to itforms an anellated imidazole ring; or a stereoisomer thereof, or aphysiologically acceptable salt thereof, or a mixture of two or more ofany of the foregoing; and one or more pharmaceutically acceptablecarriers.
 25. A composition useful for the treatment or prevention ofcardiovascular diseases, endothelial dysfunction, diastolic dysfunction,atherosclerosis, hypertension, angina pectoris, thromboses, restenoses,myocardial infarction, strokes, cardiac insufficiency, pulmonaryhypertonia, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency, diabetes or cirrhosis of the liver, said compositioncomprising an amount efficacious for said treatment or prevention of acompound of formula I as claimed in claim 1, a stereoisomeric formthereof, or a physiologically acceptable salt thereof, or a mixture oftwo or more of any of the foregoing, and one or more pharmaceuticallyacceptable carriers.
 26. A method for activating soluble guanylatecyclase, said method comprising the step of administering an amountefficacious therefor of a compound of formula I as claimed in claim 1, astereoisomeric form thereof, a physiologically acceptable salt thereof,or a mixture of any two or more of the foregoing.
 27. The method asclaimed in claim 26, further comprising the step of diagnosing adisease.
 28. The method as claimed in claim 26, wherein saidadministering is to a human or animal patient in need of suchactivating.
 29. A method for treatment or prevention of cardiovasculardiseases, endothelial dysfunction, diastolic dysfunction,atherosclerosis, hypertension, angina pectoris, thromboses, restenoses,myocardial infarction, strokes, cardiac insufficiency, pulmonaryhypertonia, erectile dysfunction, asthma bronchiale, chronic kidneyinsufficiency, diabetes, or cirrhosis of the liver in a human or animalpatient, said method comprising the step of administering to the patientan amount efficacious for said treatment or prevention of a compound offormula I as claimed in claim 1, a stereoisomeric form thereof, aphysiologically acceptable salt thereof, or a mixture of any two or moreof the foregoing.
 30. A method for improving restricted memoryperformance or ability to learn in a human or animal patient, saidmethod comprising the step of administering an amount efficacioustherefor to the patient of a compound of formula I as claimed in claim1, a stereoisomeric form thereof, a physiologically acceptable saltthereof, or a mixture of any two or more of the foregoing.